WO2004087075A2 - Compositions et methodes de traitement du cancer - Google Patents

Compositions et methodes de traitement du cancer Download PDF

Info

Publication number
WO2004087075A2
WO2004087075A2 PCT/US2004/009667 US2004009667W WO2004087075A2 WO 2004087075 A2 WO2004087075 A2 WO 2004087075A2 US 2004009667 W US2004009667 W US 2004009667W WO 2004087075 A2 WO2004087075 A2 WO 2004087075A2
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
alkyl
amide
neoplastic agent
group
Prior art date
Application number
PCT/US2004/009667
Other languages
English (en)
Other versions
WO2004087075A3 (fr
Inventor
Mark Matteucci
Photon Rao
Jian-Xin Duan
Original Assignee
Threshold Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to AU2004226338A priority Critical patent/AU2004226338C1/en
Priority to CA2520000A priority patent/CA2520000C/fr
Priority to NZ543223A priority patent/NZ543223A/en
Priority to EP13178249.2A priority patent/EP2671581B8/fr
Priority to KR1020127002215A priority patent/KR101198526B1/ko
Priority to JP2006509466A priority patent/JP2006521409A/ja
Priority to EP04749522A priority patent/EP1622608A4/fr
Priority to MXPA05010407A priority patent/MXPA05010407A/es
Application filed by Threshold Pharmaceuticals, Inc. filed Critical Threshold Pharmaceuticals, Inc.
Priority to US10/549,545 priority patent/US7550496B2/en
Publication of WO2004087075A2 publication Critical patent/WO2004087075A2/fr
Publication of WO2004087075A3 publication Critical patent/WO2004087075A3/fr
Priority to IL170970A priority patent/IL170970A/en
Priority to NO20054988A priority patent/NO336266B1/no
Priority to US12/484,104 priority patent/US8299088B2/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/559—Redox delivery systems, e.g. dihydropyridine pyridinium salt redox systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6891—Pre-targeting systems involving an antibody for targeting specific cells
    • A61K47/6899—Antibody-Directed Enzyme Prodrug Therapy [ADEPT]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members

Definitions

  • Cancer generally refers to one of a group of more than 100 diseases caused by the uncontrolled growth and spread of abnormal cells that can take the form of solid tumors, lymphomas, and non-solid cancers such as leukemia. Unlike normal cells, which reproduce until maturation is attained and then only as necessary for replacement, cancer cells grow and divide endlessly, crowding out nearby cells and eventually spreading to other parts of the body, unless their progression is stopped. Once cancer cells metastasize by leaving a tumor, they will travel through the bloodstream or lymphatic system to other parts of the body, where the cells begin multiplying and developing into new tumors. This sort of tumor progression makes cancer dangerously fatal. Although there have been great improvements in diagnosis, general patient care, surgical techniques, and local and systemic adjuvant therapies, most deaths from cancer are still due to metastases and other cancers that are resistant to conventional therapies including radiation and chemotherapy.
  • Radiotherapy is typically only effective for cancer treatment at early and middle stages of cancer, when cancer is localized, and not effective for late stage disease with metastasis.
  • Chemotherapy can be effective at all stages of the disease, but there can be severe side effects, e.g. vomiting, low white blood cells, loss of hair, loss of weight and other toxic effects, to radiation therapy and chemotherapy. Because of such severe side effects, many cancer patients do not or cannot successfully complete a chemotherapy treatment regimen.
  • the side effects of radiation and anticancer drugs can be viewed as resulting from poor target specificity.
  • Anticancer drugs typically administered intravenously or more rarely orally, circulate through most normal tissues of patients as well as the target tumors.
  • Prodrugs have been investigated as a means to lower the unwanted toxicity or some other negative attribute of a drug without loss of efficacy.
  • a prodrug is a drug that has been chemically modified to render it inactive but that, subsequent to administration, is metabolized or otherwise converted to the active form of the drug in the body.
  • prodrugs have been developed that are activated under hypoxic conditions. Hypoxia creates a bioreductive environment, and certain anti-cancer agents have been converted into prodrugs that can be activated in such environments. See the reviews by Naylor et al., May 2001, Mini. Rev. Med. i(l):17-29, and Denny, 2001, Eur. J. Med Chem.
  • Hypoxia is a condition of low oxygen levels; most solid tumors larger than about 1 mm in diameter contain hypoxic regions (see the references Coleman, 1988, J. Nat. Cane. Inst. 80: 310; and Vaupel et ah, Cancer Res. 49: 6449).
  • vascular architecture of the tumor can contribute significantly to the cancer's ability to survive drug therapy in at least two different ways. First, if the drug must reach the cancer through the bloodstream, then not as much drug will reach the under- vascularized, hypoxic areas of the tumor. Second, to the extent the drug requires oxygen to be effective, then the drug will be less effective in the hypoxic regions of the tumor.
  • bioreductive prodrug compounds have been developed to exploit such environments.
  • These prodrugs include the antibiotics Mitomycin C (MMC) and Porfiromycin (POR), N-oxides such as Tirapazamine (TRZ; see the reference Zeeman et al, 1986, Inst. J. Radiot. Oncol. Biol Phys. 12: 1239), quinones such as the indoloquinone E09 (see the reference Bailey et al, 1992, Int. J.
  • bioreductively activated prodrug compounds include the nitroimidazole derivatives that have been reported to be useful in cancer radiotherapy as radio-sensitizing agents (see the patent publications EP312858 and WO91/11440) and potentiatiors of chemotherapeutic agents (see U.S. Patent No. 4,921,963).
  • Nitroimidazole has also been conjugated to the anti-cancer agent PARP 5-bromoisoquinolinone (see the reference Parveen et al., Jul. 1999, Bioorg. Med. Chem. Lett., 9:2031-36).
  • the nitroimidazole moiety itself is, however, somewhat cytotoxic to normal cells, because it undergoes redox cycling and generates superoxides under oxygenated conditions.
  • Bioreductively activated prodrug compounds that include a nitroimidazole linked to a variety of anti-neoplastic agents has been described in A 2-NITROIMIDAZOLE CARBAMATE PRODRUG OF 5-AMINO-l-(CHLOROMETHYL)-3-[5,6,7- TRIMETHOXYINDOL-2-YL)CARBONYL]-l,2-DIHYDRO-3H-BENZ[E]INDOLE (AMINO-SECO-CBI-TMI) FOR USE WITH ADEPT AND GDEPT, M.P. Hay et al., Bioorganic & Medicinal Chemistry Letters 9 (1999) 2237-2242, and PCT publication WO 00/64864.
  • the nitroimidazole is directly linked to a carbamate linker and the anti-neoplastic agent is protected at a nitrogen via a carbamate or at a carbon via an ester linkage.
  • Described in the patent are compounds, compositions, and methods for treating cancer.
  • Re is unsubstituted alkyl or alkyl substituted with one or more heteroatom containing groups
  • R 7 is hydrogen, unsubstituted alkyl or alkyl substituted with one or more heteroatom containing groups
  • the hypoxic activator may be an electron deficient nitrobenzene moieties, electron deficient nitrobenzoic acid amide moieties, nitroazole moieties, nitroimidazole moieties, nitrothiophene moieties, nitrothiazole moieties, nitrooxazole moieties, nitrofuran moieties, and nitropyrrole moieties, hi one version, the hypoxic activator is a substituted or unsubstituted nitroimidazole moiety.
  • hypoxic activator is a moiety of the formula
  • hypoxic activator is a moiety of the formula
  • R 2 is hydrogen; R 3 is hydrogen or C ⁇ -C 6 alkyl; Ri is unsubstituted - alkyl, C ⁇ -C 6 alkyl substituted with one or more heteroatom-containing groups, unsubstituted C ⁇ -C 6 alkoxy, or C ⁇ -C 6 alkoxy substituted with one or more heteroatom-containing groups; and Ri is -H, unsubstituted C ⁇ -C 6 alkyl, C ⁇ -C 6 alkyl substituted with one or more heteroatom-containing groups, unsubstituted C ⁇ -C alkoxy, or C ⁇ -C 6 alkoxy substituted with one or more heteroatom-containing groups. Specific substitution for alkyl and alkoxy are described in detail in the Detail Description.
  • hypoxic activator is a nitrobenzene of formula
  • R 2 is hydrogen; R 3 is -H, C ⁇ -C 6 alkyl; and R 50 , R 5 ⁇ , R52 , and R 53 are independently selected from an electron withdrawing group, H, C 1-6 alkyl or C 1-6 alkoxy; where the alkyl and alkoxy are optionally independently substituted with one or more groups. Specific electron withdrawing groups and substitution for alkyl and alkoxy are described in detail in the Detail Description.
  • the anti-neoplastic agent is bonded to the hypoxic activator (Hyp) or linking group (L) through an hydroxyl oxygen or amine nitrogen in the anti-neoplastic agent.
  • the anti-neoplastic agent is bonded to the hypoxic activator (Hyp) or linking group (L) by an -O- group
  • the -O- group may be bonded to an aromatic group in the anti-neoplastic agent, and that aromatic group may be a substituted or unsubstituted phenyl.
  • anti-neoplastic agents examples include but are not limited to doxorubicin, daunorubicin, duocarmycin, etoposide, duetoposide, Combretastatin A-4, vinblastine, vincristine, camptothecin, topotecan, 5-fluorouracil, AQ4N, hydroxyurea, maytansines, enediyenes, discodermolides, epothilones, taxanes, calicheamicins, tedanolides, bleomycins, calicheamicins, colchicine, cytarabine, dacarbazine, dactinomycin, discodermolides, epirubicin, epirubicin derivatives, fludarabine, hydroxyureapentostatin, 6- mercaptopurine, methotrexate, mitomycin, mitoxantrone, carboplatin, cisplatin, prednisone, proc
  • the compound released upon reduction of the hypoxic activator may have an ICs 0 of less than about lOOnM.
  • X is the ether group and Y is -(CR c R d )- where R c and R d are independently hydrogen, unsubstituted alkyl, or alkyl substituted with one or more of heteroatom containing groups.
  • R c and R d are hydrogen.
  • R c and R d are hydrogen and Y is attached to the anti-neoplastic agent via an oxygen of a hydroxyl group in the anti-neoplastic agent.
  • X and Y are as in the previous sentence and Y is attached to the anti-neoplastic agent via an nitrogen of an amine group in the anti-neoplastic agent.
  • R ⁇ is unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl, where the substituted aryl or substituted heteroaryl are independently substituted with one or more groups selected from an electron withdrawing group, unsubstituted C ⁇ -C 6 alkyl, substituted C ⁇ -C 6 alkyl, unsubstituted Ci-C ⁇ alkoxy, and substituted C ⁇ -C 6 alkoxy; where the substituted alkyl or alkoxy are independently substituted with one or more groups selected from ether (-OR ), amino (-NH 2 ), mono-substituted ammo
  • R ⁇ is substituted or unsubstituted pyridyl, pyridazinyl, and pyrimidinyl. In another version, R ⁇ is substituted or unsubstituted phenyl.
  • Y has the formula
  • each of R ⁇ 3 -R 2 oare independently selected from hydrogen, an electron withdrawing group, unsubstituted Ci-C ⁇ alkyl, substituted C ⁇ -C 6 alkyl, unsubstituted C ⁇ -C 6 alkoxy, and substituted C ⁇ -C 6 alkoxy; where the substituted alkyl or alkoxy are independently substituted with one or more groups.
  • Specific electron withdrawing groups and substitution for alkyl and alkoxy are described in detail in the Detail Description.
  • the linking group L has the formula
  • the protected anti-neoplastic agents may be used for treating cancer by administering to a subject a therapeutically effective amount of a protected anti-neoplastic agent.
  • the protected anti-neoplastic agent may be administered alone or in combination with an effective amount of one or more chemotherapeutic agents, an effective amount of radiotherapy, a surgery procedure, or any combination of the foregoing.
  • Chemotherapeutic agents that may be used are described in detail in the Detailed Description section.
  • Cancers that may be treated are described in detail in the Detailed Description section and include lung cancer, non-small cell lung cancer, breast cancer, colon cancer, head and neck cancer, ovarian cancer, pancreatic cancer, and prostate cancer.
  • alkyl includes any aliphatic group containing carbon and hydrogen including, straight chain, branched chain, cyclic, and carbocycle containing alkyl groups.
  • an "anti-neoplastic agent”, “anti-tumor agent”, or “anti-cancer agent” refers generally to any agent used in the treatment of cancer. Such agents can be used alone or in combination with other compounds and can alleviate, reduce, ameliorate, prevent, or place or maintain in a state of remission of clinical symptoms or diagnostic markers associated with neoplasm, tumor or cancer.
  • Anti-neoplastic agents include, but are not limited to, anti-angiogenic agents, alkylating agents, antimetabolites, microtubulin polymerization perturbers (for example, Taxol), certain natural products, platinum coordination complexes, anthracenediones, substituted ureas, methylhydrazine derivatives, adrenocortical suppressants, certain hormones and antagonists, anti-cancer polysaccharides and certain herb or other plant extracts.
  • microtubulin polymerization perturbers for example, Taxol
  • certain natural products platinum coordination complexes, anthracenediones, substituted ureas, methylhydrazine derivatives, adrenocortical suppressants, certain hormones and antagonists, anti-cancer polysaccharides and certain herb or other plant extracts.
  • an "anti-neoplastic treatment” refers to any approach for ameliorating the symptoms of or delaying the progression of a neoplasm, tumor, or cancer by reducing the number of or growth of cancer cells in the body, typically (but not limited to) by killing or halting the growth and division of cancer cells.
  • bioreductive compound refers to a compound that accepts electrons in an oxidation-reduction reaction.
  • cancer refers to one of a group of more than 100 diseases caused by the uncontrolled growth and spread of abnormal cells that can take the form of solid tumors, lymphomas, and non-solid cancers such as leukemia.
  • malignant refers to cells that have the capacity of metastasis, with loss of both growth and positional control.
  • neoplasm neoplasia
  • tumor refers to abnormal new cell or tissue growth, which may be benign or malignant.
  • a prodrug is a compound that, after administration, is metabolized or otherwise converted to an active or more active form with respect to at least one property.
  • a pharmaceutically active compound can be modified chemically to render it less active or inactive, but the chemical modification is such that an active form of the compound is generated by metabolic or other biological processes.
  • a prodrug may have, relative to the drug, altered metabolic stability or transport characteristics, fewer side effects or lower toxicity, or improved flavor, for example (see the reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392).
  • Prodrugs can also be prepared using compounds that are not drugs.
  • the protected anti-neoplastic agent has the formula Hyp-L-N or Hyp-N, where Hyp is a hypoxic activator; L is a linking group; and N is an anti-neoplastic agent.
  • the various hypoxic activators, linking groups and anti-neoplastic agents that may be used in these protected anti-neoplastic agents are described in the hypoxic activator, linking group, and anti-neoplastic agent sections below.
  • the protected anti-neoplastic agent is an anti-neoplastic agent in which one or more hydroxyl and/or amine groups present in the anti-neoplastic agent are protected by a hypoxic activator group, Hyp, which is bonded directly to the amine or hydroxyl group either directly or through a linker group, L.
  • a hypoxic activator group Hyp
  • Anti-neoplastic agents, hypoxic activators and linking groups that may be used are described in the anti-neoplastic agents, Hypoxic activator and Linking group sections below.
  • the hydrogen in the hydroxyl group or one or more of the moieties attached to the nitrogen in the amine group are replaced by a bond to the protecting group, i.e., by a bond to the Hyp-group or to the Hyp-L- group.
  • the amine is a primary amine and one of the hydrogens is replaced by the protecting group.
  • anti-neoplastic agent protected anti-neoplastic agent
  • any number of amine and any number of hydroxyl groups in an anti-neoplastic agent may be protected.
  • one amine group in an anti-neoplastic agent is protected.
  • one hydroxyl in an anti-neoplastic agent is protected. If more than one hydroxyl and/or amine group is protected in an anti-neoplastic agent, the protecting groups can be the same or can be different.
  • the protected group in the anti-neoplastic agent is a hydroxyl group that is attached to an aromatic or heteroaromatic ring in the anti-neoplastic agent.
  • the aromatic or heteroaromatic ring may be substituted or unsubstituted and may be fused with one or more additional rings, which may be aromatic or nonaromatic and may contain any number of hetero ring atoms.
  • the protected hydroxyl is attached to a phenyl ring in the anti-neoplastic agent, and the phenyl ring may be substituted or unsubstituted and may be fused with one or more additional rings, which may be aromatic or nonaromatic and may contain any number of hetero ring atoms.
  • the protected amine or protected hydroxyl may be bonded either directly to any hypoxic activator or bonded to any hypoxic activator via any linking group described in the patent.
  • hydroxyl and amine groups in an anti-neoplastic agent may be protected by attachment to a hypoxic activator, either directly or through a linker.
  • Other groups that may be protected include sulfur based groups, aldehydo groups, and keto groups.
  • Protected Anti-neoplastic agents can release Anti-neoplastic agent or Modified Anti-neoplastic agent, Including "Super Toxins": Depending on whether the anti-neoplastic agent is bonded directly to the hypoxic activator and depending on the nature of the linking group if the anti-neoplastic agent is bonded via a linking group to the hypoxic activator, the molecule released upon reduction of the hypoxic activator is either the anti-neoplastic agent or a modified anti-neoplastic agent that includes some or all of the linking group attached to the anti-neoplastic agent.
  • a "modified anti-neoplastic agent” refers to a species that is released from a protected anti-neoplastic agent and that is different from the anti-neoplastic agent itself.
  • a protected anti-neoplastic agent with formula Hyp- L-N may yield a modified anti-neoplastic agent of formula L-N upon reduction of the hypoxic activator.
  • the linking group attached to the anti-neoplastic agent may undergo rearrangement or degradation to yield either the unmodified anti-neoplastic agent or some other modified anti-neoplastic agent.
  • That the molecule released upon reduction of the hypoxic activator may be different from the anti-neoplastic agent being protected will be appreciated by those of skill in the art. This is illustrated in the Examples below, one of which shows that a protected anti-neoplastic agent can be synthesized by linking doxorubicin to a hypoxic activator to form a protected anti-neoplastic agent that releases an iminium-containing doxorubicin derivative that is far more toxic than doxorubicin.
  • the protected anti-neoplastic agents described in this patent generally exhibit greater efficacy and/or fewer side effects than prior compounds.
  • certain protected anti-neoplastic agents described in this patent are conjugated to, or are activated by hypoxic conditions to release very powerful cytotoxic agents, "super toxins" with ICso values of less than 100 nM against a majority of the cancer cell lines in the NCI tumor cell line panel.
  • the protected anti-neoplastic agents described in this patent that release "super toxins” can be used in much lower doses than the nitroimidazole prodrugs heretofore known. These lower doses produce less superoxide (see discussion below) in normoxic tissue.
  • the protected anti-neoplastic agents can be used to release a wide variety of anti- neoplastic agents as is described in the Anti-neoplastic agent section in this patent.
  • Protected Anti-neoplastic agents may have reduced Toxicity: The protected anti- neoplastic agents, relative to the drugs to which they are converted in vivo, maybe much less (at least ten and up to one million-fold less) toxic. The reduced toxicity results from a modification at the site of attachment of the linker L (as in the case where activation of the protected anti-neoplastic agents releases the same cytotoxic agent that was used in the synthesis of the drug) or from the generation of a moiety required for toxicity by removal of the hypoxic activator (Hyp).
  • Hyp hypoxic activator
  • the protected anti-neoplastic agents are converted into the corresponding toxic drug in hypoxic tissues by virtue of the activation of the hypoxic activator moiety, resulting in its removal and the concomitant release or generation of the anti-neoplastic agent or a modified version of the anti-neoplastic agent.
  • the linker and hypoxic activator moiety are attached to the anti-neoplastic agent, N, in a manner that masks or reduces the cytotoxic activity of the anti-neoplastic agent.
  • This masking effect can vary and may depend on the cytotoxic activity of the anti-neoplastic agent to be released.
  • the protected anti-neoplastic agent will show at least about 10 fold less cytotoxic activity than the anti- neoplastic agent, and may show up to about a million fold or more or less cytotoxic activity.
  • the cytotoxic activity of the protected anti-neoplastic agent is about 100 fold to about 10,000 fold less than the cytotoxic activity of the anti-neoplastic agent.
  • the corresponding IC 50 of the protected anti-neoplastic agent can be 1 microM or greater.
  • the Protected Anti-neoplastic agents described in this patent include as anti-neoplastic agents, N, any agent that can be linked to a hypoxic activator in a manner that yields a protected anti-neoplastic agent that is at least about 10-fold to about 1,000,000- fold, and typically about 100 to about 10,000-fold, less active as a cytotoxic agent than the anti-neoplastic agent or modified anti-neoplastic agent that is released from the Protected Anti-neoplastic agent under hypoxic conditions.
  • N any agent that can be linked to a hypoxic activator in a manner that yields a protected anti-neoplastic agent that is at least about 10-fold to about 1,000,000- fold, and typically about 100 to about 10,000-fold, less active as a cytotoxic agent than the anti-neoplastic agent or modified anti-neoplastic agent that is released from the Protected Anti-neoplastic agent under hypoxic conditions.
  • Nitroimidazoles have previously been used to form prodrugs for some putative anti-cancer agents, including a PARP inhibitor (see the reference Parveen et al., 1999, Bioorganic and Medicinal Letters 9: 2031- 2036) a nitrogen mustard, which was activated, not released, by the nitroimidazole (see the reference Lee et al., 1998, Bioorganic and Medicinal Letters 8: 1741-1744) and the agents described in the A 2-NITROIMIDAZOLE CARBAMATE PRODRUG OF 5- AMINO-l-(CHLOROMETHYL)-3-[5,6,7-TRIMETHOXYINDOL-2-YL)CARBONYL]- l,2-DIHYDRO-3H-BENZ[E]INDOLE (AMINO-SECO-CBI-TMI) FOR USE WITH ADEPT AND GDEPT, M.P.
  • PARP inhibitor see the reference Parveen et al., 1999, Bioorganic and Medicinal Letter
  • the Protected Anti-neoplastic agents described in this patent differ from such known prodrugs in various ways including but not limited to the nature of the anti-neoplastic agent released, the nature of the linking of the hypoxic activator to the anti-neoplastic agent the better side effect profile, the presence of more than one hypoxic activator moiety, or some combination of these attributes. Without being bound by theory, these advantages of the protected anti-neoplastic agents can be better appreciated with an understanding of the pharmacokinetics of hypoxia-activated prodrugs generally and the protected anti-neoplastic agents described in this patent in particular.
  • the protected anti-neoplastic agent includes a nitroimidazole as the hypoxic activator.
  • Nitroimidazole is, in the absence of oxygen, converted to a free radical containing moiety by a cytochrome P450 reductase. If the nitroimidazole is appropriately covalently bound to another moiety, further reduction of the free radical form of nitroimidazole can lead to release of that moiety. However, in the presence of oxygen, the free radical reacts with oxygen to form superoxide and the parent nitroimidazole. Superoxide is a cytotoxin, so the production of superoxide in normoxic tissues is believed to lead to unwanted side effects.
  • Certain nitroimidazole-containing prodrugs can also be activated regardless of the oxygen tension by DT diaphorase, which can lead to activation in normoxic cells, thus contributing to unwanted side effects. Should this normoxic activation pathway create significant side effects with a particular protected anti-neoplastic agent, however, one can select another protected anti-neoplastic agent that contains more than one hypoxia-activated moiety to reduce or eliminate such side effects.
  • hypoxic activator in which the hypoxic activator is a nitroimidazole, the hypoxic activator is activated under hypoxic conditions through the nitro group being reduced to a hydroxylamine or an amine with concomitant release of the portion of the molecule to which the hypoxic activator is attached.
  • This activation process is shown in the following scheme. Although the scheme shown illustrates an ether linkage between the hypoxic activator and the remainder of the protected anti-neoplastic agent, similar mechanisms will apply for the acetal groups to which the hypoxic activator is attached.
  • hypoxic activator For a protected anti-neoplastic agent containing a nitroimidazole as the hypoxic activator, reduction of the hypoxic activator will release at least initially an aldehyde when the hypoxic activator is attached to an acetal group and will release, at least initially, an alcohol when the hypoxic activator is attached to an ether group.
  • the following scheme presents a mechanism for release from one version of a hypoxic activator.
  • the hypoxic activator can be any group that is capable of releasing the anti-neoplastic agent or a modified version of the anti-neoplastic agent upon hypoxic reduction of the hypoxic activator.
  • the hypoxic activator is a group that is capable of releasing the anti-neoplastic agent or a modified version of the anti-neoplastic agent upon reduction of the hypoxic activator under hypoxic conditions but that does not release substantially any anti-neoplastic agent or a modified version of the anti-neoplastic agent under normoxic conditions.
  • hypoxic activators include but are not limited to moieties based on electron deficient nitrobenzenes, electron deficient nitrobenzoic acid amides, nitroazoles, nitroimidazoles, nitrothiophenes, nitrothiazoles, nitrooxazoles, nitrofurans, and nitropyrroles where each of these classes of moieties may be substituted or unsubstituted.
  • the hypoxic activator is substituted nitroimidazole.
  • the hypoxic activator is substituted nitrobenzene.
  • hypoxic activator is a nitroimidazole that may be substituted with a variety of groups.
  • the thiophene, furan thiazole, and moieties may be substituted with one or more electron donating groups, including but not limited to methyl or methoxy or amine groups to achieve the desired range of redox potential.
  • the nitropyrrole moiety may require substitution of electron withdrawing group including but not limited to cyano, carboxamide, -CF3, and sulfonamide groups to achieve the desired range of redox potential.
  • electron withdrawing group including but not limited to cyano, carboxamide, -CF3, and sulfonamide groups.
  • electron withdrawing groups including but not limited to cyano, carboxamide, -CF3, and sulfonamide groups
  • hypoxic activator is a nitroimidazole
  • hypoxic activator has the formula
  • hypoxic activator has the formula
  • R is hydrogen; R 3 is -H or C ⁇ -C 6 alkyl; Ri is selected from an C ⁇ -C 6 alkyl, or C C 6 alkoxy, where the alkyl or alkoxy is optionally substituted with one or more heteroatom-containing groups; and R is selected from -H, C1-C 5 alkyl, or C ⁇ -C 6 alkoxy, where the alkyl or alkoxy is optionally substituted with one or more heteroatom-containing groups.
  • R 2 is hydrogen; R 3 is -H or C ⁇ -C 6 alkyl; Ri is alkyl, where the alkyl is optionally substituted with one or more heteroatom-containing groups; and R 4 is selected from -H, or C ⁇ -C 6 alkyl, where the alkyl is optionally substituted with one or more heteroatom-containing groups.
  • R 2 is hydrogen;
  • R 3 is -H or C C ⁇ alkyl; and
  • Ri and t are each independently -H, or C ⁇ -C 6 alkyl; where the alkyl is optionally substituted with one or more heteroatom-containing groups selected from hydroxyl, ether, thiol, thioether, sulfinic ester, sulfoxide, sulfone, sulfonic acid, sulfonic acid ester, sulfenamide, sulfonamide, carboxylic acid, carboxylic acid salt, ester, amide , aldehydo, keto, amino, halo, and cyano; preferably hydroxyl, ether, thiol, thioether, carboxylic acid, carboxylic acid salt, ester, amide , aldehydo, keto, amino, halo, and cyano; preferably hydroxyl, ether, thiol, thioether, carboxylic acid, carboxy
  • R 2 is hydrogen;
  • R 3 is -H or Ci-Ce alkyl; and
  • Ri and R-j are each independently an H, Ci-Ce alkyl or C ⁇ -C 6 alkoxy, the alkyl or alkoxy being optionally substituted with one or more groups selected from ether (-OR 20 ), amino (-NH 2 ), mono- substituted amino (-NR 20 H), di-substituted amino (-NR 21 R 22 ), cyclic C1.
  • R 2 is hydrogen;
  • R 3 is -H or C ⁇ -C 3 alkyl; and
  • R ⁇ and Ri are each independently an -H or alkyl selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, t-butyl, cyclohexyl, cyclopentyl, and isopropyl, where the alkyl is optionally substituted with one or more heteroatom-containing groups; with the proviso that Ri is not hydrogen.
  • R 2 is hydrogen;
  • R 3 is -H or C ⁇ -C 3 alkyl; and
  • Ri and R 4 are each independently -H or alkyl selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, t-butyl, cyclohexyl, cyclopentyl, and isopropyl, where the alkyl is optionally substituted with one or more heteroatom-containing groups selected from hydroxyl, ether, thiol, thioether, sulfinic ester, sulfoxide, sulfone, sulfonic acid, sulfonic acid ester, sulfenamide, sulfonamide, carboxylic acid, carboxylic acid salt, ester, amide , aldehydo, keto, amino, halo, and cyano; preferably hydroxyl, ether,
  • R 2 is hydrogen;
  • R 3 is -H or C ⁇ -C 3 alkyl; and
  • Ri and Rt are each independently -H or alkyl selected from methyl, ethyl, n- propyl, n-butyl, n-pentyl, t-butyl, cyclohexyl, cyclopentyl, and isopropyl, where the alkyl is optionally substituted with one or more heteroatom-containing groups selected from ether (- on on oi i
  • R 2 is hydrogen; R 3 is -H or C ⁇ -C 3 alkyl; and Ri and R 4 are each independently selected from methyl, ethyl, n-propyl, or n-butyl, each alkyl optionally substituted by a heteroatom containing group, particularly an amine group a carboxylic acid group, or an amide group.
  • R 2 is hydrogen and Ri and R 3 are any of the versions described above and Ri is C ⁇ -C 3 alkyl optionally substituted with a heteroatom containing group, particularly an amine group a carboxylic acid group, or an amide group.
  • R 2 is hydrogen and Ri , R 3 , and Ri are each independently ethyl, n-propyl, or n-butyl, each optionally substituted by a heteroatom containing group, particularly an amine group a carboxylic acid group, or an amide group
  • R 2 is hydrogen;
  • R 3 is hydrogen or C ⁇ -C 3 alkyl;
  • Ri is methyl, methylacetate, or ethyl, n-propyl, or n-butyl, each optionally substituted with an amine group, a carboxylic acid group, or an amide group, and
  • t is hydrogen or C ⁇ -C alkyl.
  • R 2 is hydrogen;
  • R 3 is hydrogen or C ⁇ -C 3 alkyl;
  • Ri is methyl, methylacetate, or ethyl, n-propyl, or n-butyl, each optionally substituted with an amine group, a carboxylic acid group, or an amide group, and i is hydrogen.
  • R 2 is hydrogen, Ri is an alkyl group bearing steric hinderance and R 3 , and R-t are each independently -H or C ⁇ -C 6 alkyl, optionally substituted with one or more heteroatom-containing groups.
  • R 2 is hydrogen, Ri is methyl and R 3 , and Ri are each independently -H or C ⁇ -C 6 alkyl, optionally substituted with one or more heteroatom-containing groups.
  • R 2 is hydrogen, Ri is methylacetate and R 3 , and R 4 are each independently -H or C ⁇ -C 6 alkyl, optionally substituted with one or more heteroatom-containing groups.
  • Ri , R 3 , and j are any of the versions described above and R 2 is selected from -H or C 1-6 alkyl, optionally substituted with one or more heteroatom containing groups.
  • Ri , R 3 , and R 4 are any of the versions described above and R is -H, methyl, n-pentyl, t-butyl, cyclohexyl, cyclopentyl, or isopropyl, all optionally substituted with one or more heteroatom-containing groups selected from hydroxyl, ether, thiol, thioether, sulfinic ester, sulfoxide, sulfone, sulfonic acid, sulfonic acid ester, sulfenamide, sulfonamide, carboxylic acid, carboxylic acid salt, ester, amide , aldehydo, keto, amino, halo, and cyano; preferably hydroxyl, ether, thiol, thioether, carboxylic acid, carboxylic acid salt, ester, amide , aldehydo, keto, amino, halo, and cyano.
  • the heteroatom substituent on an alkyl group may in one version be on the beta position of the alkyl group.
  • ethyl may be substituted with methoxy at the beta position to give -(CH 2 )-CH 2 -0-CH 3 .
  • hypoxic activator is a nitroimidazole
  • hypoxic activator has the formula
  • hypoxic activator has the formula
  • R 2 is hydrogen; R 3 is -H or C ⁇ -C 6 alkyl; Ri is selected from an electron withdrawing group, C ⁇ -C 6 alkyl, or Ci-C ⁇ alkoxy, where the alkyl or alkoxy is optionally substituted with one or more heteroatom- containing groups; and R_ ⁇ is selected from an electron withdrawing group, -H, C ⁇ -C 6 alkyl, or Ci-C 6 alkoxy, where the alkyl or alkoxy is optionally substituted with one or more heteroatom-containing groups.
  • at least one of RI and R4 is an electron withdrawing group.
  • R is hydrogen; R 3 is -H or Ci-C ⁇ alkyl; R t is selected from an electron withdrawing group, or -C ⁇ alkyl, where the alkyl is optionally substituted with one or more heteroatom-containing groups; and Rj is selected from an electron withdrawing group, -H, or C ⁇ -C 6 alkyl, where the alkyl is optionally substituted with one or more heteroatom-containing groups.
  • at least one of RI and R4 is an electron withdrawing group.
  • R 2 is hydrogen;
  • R 3 is -H or Ci-C ⁇ alkyl; and
  • Ri and R 4 are each independently an electron withdrawing group, -H, or C ⁇ -C 6 alkyl; where the alkyl is optionally substituted with one or more heteroatom-containing groups selected from hydroxyl, ether, thiol, thioether, sulfinic ester, sulfoxide, sulfone, sulfonic acid, sulfonic acid ester, sulfenamide, sulfonamide, carboxylic acid, carboxylic acid salt, ester, amide , aldehydo, keto, amino, halo, and cyano; preferably hydroxyl, ether, thiol, thioether, carboxylic acid, carboxylic acid salt, ester, amide , aldehydo, keto, amino, halo, and cyano; preferably hydroxyl, ether, thiol, thioether,
  • RI and R4 are each electron withdrawing group.
  • R 2 is hydrogen;
  • R 3 is -H or C ⁇ -C 6 alkyl;
  • Ri and j are each independently an electron withdrawing group, H, C1- C 6 alkyl or C ⁇ -C 6 alkoxy, the alkyl or alkoxy being optionally substituted with one or more groups selected from ether (-OR ), amino (-NH 2 ), mono-substituted amino (-NR H), disubstituted amino (-NR 21 R 22 ), cyclic C 1-5 alkylamino, imidazolyl, Ci -6 alkylpiperazinyl, morpholino, thiol (-SH), thioether -(SR ), tetrazole, carboxylic acid (-COOH), ester (- COOR 20 ), amide (-CONH 2
  • R 2 is hydrogen;
  • R 3 is -H or Ci-C 3 alkyl; and
  • Ri and Rj are each independently an electron withdrawing group, -H or alkyl selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, t-butyl, cyclohexyl, cyclopentyl, and isopropyl, where the alkyl is optionally substituted with one or more heteroatom-containing groups; where the electron withdrawing group is selected from halo, on cyano (-CN), haloalkyl, carboxamide, nitro, aldehydo (-CHO), keto (-COR ), alkenyl, alkynyl, quaternary amino (-NW ⁇ 22 ), ester (-COOR 20 ), amide (-CONH 2 ), mono- substituted amide (-CONHR 20 ), disubsti
  • R 2 is hydrogen;
  • R 3 is -H or C ⁇ -C 3 alkyl; and
  • Ri and t are each independently an electron withdrawing group, -H or alkyl selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, t-butyl, cyclohexyl, cyclopentyl, and isopropyl, where the alkyl is optionally substituted with one or more heteroatom-containing groups selected from hydroxyl, ether, thiol, thioether, sulfinic ester, sulfoxide, sulfone, sulfonic acid, sulfonic acid ester, sulfenamide, sulfonamide, carboxylic acid, carboxylic acid salt, ester, amide , aldehydo, keto, amino, halo, and cyano; preferably hydroxy
  • R is hydrogen;
  • R 3 is -H or Ci-C 3 alkyl; and
  • Ri and t are each independently an electron withdrawing group, -H or alkyl selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, t-butyl, cyclohexyl, cyclopentyl, and isopropyl, where the alkyl is optionally substituted with one or more heteroatom-containing groups selected from ether (-OR 20 ), amino (-NH ), mono-substituted on oi oo amino (-NR H), di-substituted amino (-NR R ⁇ ), cyclic C1- 5 alkylamino, imidazolyl, C e
  • R 20 , R 21 , and R 22 are independently selected from a C ⁇ -C 6 alkyl group, a C 3 -C 20 heterocyclic group, or a C 3 -C 20 aryl group, preferably a C ⁇ -C 6 alkyl group with the proviso that Ri is not hydrogen.
  • at least one of RI and R4 is an electron withdrawing group.
  • R 2 is hydrogen;
  • R 3 is -H or Ci-C 3 alkyl; and
  • Ri and R 4 are each independently selected from cyano, haloalkyl, carboxamide, methyl, ethyl, n-propyl, or n-butyl, each optionally substituted by a heteroatom containing group, particularly an amine group a carboxylic acid group, or an amide group.
  • At least one of RI and R4 is an electron withdrawing group.
  • R is hydrogen and Ri and R 3 are any of the versions described above and R4 is C ⁇ -C 3 alkyl optionally substituted with a heteroatom containing group, particularly an amine group a carboxylic acid group, or an amide group.
  • R 2 is hydrogen and Ri ,
  • R 3 , and R 4 are each independently ethyl, n-propyl, or n-butyl, each optionally substituted by a heteroatom containing group, particularly an amine group a carboxylic acid group, or an amide group
  • R is hydrogen;
  • R 3 is hydrogen or C ⁇ -C 3 alkyl;
  • Ri is methyl, methylacetate, or ethyl, n-propyl, or n-butyl, each optionally substituted with an amine group, a carboxylic acid group, or an amide group, and
  • t is hydrogen or Ci-C 3 alkyl.
  • R 2 is hydrogen;
  • R 3 is hydrogen or C ⁇ -C 3 alkyl;
  • Ri is methyl, methylacetate, or ethyl, n-propyl, or n-butyl, each optionally substituted with an amine group, a carboxylic acid group, or an amide group, and
  • j is hydrogen.
  • R2 is hydrogen
  • Ri is an alkyl group bearing steric hinderance and R 3
  • R 4 are each independently -H or Ci-C 6 alkyl, optionally substituted with one or more heteroatom-containing groups.
  • R 2 is hydrogen
  • R ⁇ is methyl and R 3
  • Ri are each independently -H or Ci-C 6 alkyl, optionally substituted with one or more heteroatom-containing groups.
  • R 2 is hydrogen
  • Ri is methylacetate and R 3
  • Rt are each independently -H or Ci-C 6 alkyl, optionally substituted with one or more heteroatom-containing groups.
  • the hypoxic activator is selected from one of the following
  • Ri , R 2 , R 3 , and R 4 are as described in any of the versions above.
  • are any of the versions described above for any of the hypoxic activators and R 2 is selected from -H or C 1-6 alkyl, optionally substituted with one or more heteroatom containing groups.
  • Ri , R 3 , and R 4 are any of the versions described above and R is -H, methyl, n-pentyl, t-butyl, cyclohexyl, cyclopentyl, or isopropyl, all optionally substituted with one or more heteroatom-containing groups selected from hydroxyl, ether, thiol, thioether, sulfinic ester, sulfoxide, sulfone, sulfonic acid, sulfonic acid ester, sulfenamide, sulfonamide, carboxylic acid, carboxylic acid salt, ester, amide , aldehydo, keto, amino, halo, and cyano; preferably hydroxyl, ether, thiol, thioether, carboxylic acid, carboxylic acid salt, ester, amide , aldehydo, keto, amino, halo, and cyano.
  • R 2 and R are as defined in any of the versions above, and R 50 , R 5 1 , R 5 2 , and R 53 are independently an electron withdrawing group, H, C 1-6 alkyl or C 1-6 alkoxy, said alkyl or alkoxy being optionally substituted with one or more groups selected from ether (- OR 20 ), amino (-NH 2 ), mono-substituted amino (-NR 20 H), di-substituted amino (-NR 21 R 22 ), cyclic d-5 alkylamino, imidazolyl, C1- 6 alkylpiperazinyl, morpholino, thiol (-SH), thioether - (SR 20 ), tetrazole, carboxylic acid (-COOH), ester (-COOR 20 ), amide (-CONH 2 ), mono- substituted amide (-CONHR 20 ), disubstituted amide (-CONR 21 R 22 ), N-connected amide (- NH 2
  • At least one of R 50 , R 51 , R 52 , and R 53 is an electron withdrawing group. In one version, at least one of R 50 and R 52 is an electron withdrawing group. [0103] In one version, one or more of the phenyl ring carbons is replaced with a hetero atom. In one version, one of the carbon ring atoms if replaced by a nitrogen to give a pyridyl group.
  • hypoxic activator has the formula
  • R 2 , R 3 , R 50 , R 51 , R 52 , and R 53 are as described in any of the versions above.
  • at least one of R 50 , R 51 , R 52 , and R 53 is an electron withdrawing group.
  • R 52 is an electron withdrawing group.
  • one or more of the phenyl ring carbons is replaced with a hetero atom.
  • one of the carbon ring atoms if replaced by a nitrogen to give a pyridyl group.
  • the linking group links the hypoxia activator to the anti-neoplastic agent. That is, the protected anti-neoplastic agent has the formula Hyp-L-N.
  • the linking group is a group that is capable of being cleaved from the hypoxic activator upon reduction of the hypoxic activator yielding a modified neoplastic agent that is either itself a neoplastic agent or through rearrangement, degradation, or other chemical modification yields a neoplastic agent. Specific examples are included elsewhere in this patent of such rearrangements and degradations of the modified neoplastic agents resulting from cleavage from the hypoxic activator.
  • the linking group is a group of formula ⁇ 'X ywv ? w
  • X is an ether or acetal group
  • Y is a spacer group as described in more detail below.
  • -w ⁇ X y w ? ⁇ e waV y D0nc ⁇ on the X group shows the point of attachment of
  • X to the hypoxic activator and the wavy bond on the Y group shows the point of attachment of the Y group to the anti-neoplastic agent.
  • X is one of the following ether (XI) or acetal (X2) groups
  • R is unsubstituted alkyl or alkyl substituted with one or more heteroatom containing groups; and R is hydrogen, unsubstituted alkyl or alkyl substituted with one or more heteroatom containing groups.
  • R is unsubstituted C1-C1 0 alkyl or d-C 10 alkyl substituted with one or more heteroatom containing groups
  • R 7 is hydrogen, unsubstituted d-do alkyl or C ⁇ - C 10 alkyl substituted with one or more heteroatom containing groups
  • the heteroatom containing groups contain one or more of hydroxyl, ether, thiol, thioether, sulfinic ester, sulfoxide, sulfone, sulfonic acid, sulfonic acid ester, sulfenamide, sulfonamide, carboxylic acid, carboxylic acid salt, ester, amide , aldehydo, keto, amino, halo, and cyano; preferably hydroxyl, ether, thiol, thioether, carboxylic acid, carboxylic acid salt, ester, amide , aldehydo
  • R ⁇ is unsubstituted Ci-do alkyl.
  • Re is unsubstituted d-C 3 alkyl or C ⁇ -C 3 alkyl substituted with one or more heteroatom containing groups
  • R 7 is hydrogen, unsubstituted C ⁇ -C 3 alkyl or d-C 3 alkyl substituted with one or more heteroatom containing groups, where for both Re and R 7 the heteroatom containing groups contain one or more of hydroxyl, ether, thiol, thioether, sulfinic ester, sulfoxide, sulfone, sulfonic acid, sulfonic acid ester, sulfenamide, sulfonamide, carboxylic acid, carboxylic acid salt, ester, amide , aldehydo, keto, amino, halo, and cyano; preferably hydroxyl, ether, thiol, thioether, carboxylic acid, carb
  • R 7 is hydrogen, and R is unsubstituted C ⁇ -C 3 alkyl or d-C 3 alkyl substituted with one or more heteroatom containing groups selected from hydroxyl, ether, thiol, thioether, sulfinic ester, sulfoxide, sulfone, sulfonic acid, sulfonic acid ester, sulfenamide, sulfonamide, carboxylic acid, carboxylic acid salt, ester, amide , aldehydo, keto, amino, halo, and cyano; preferably hydroxyl, ether, thiol, thioether, carboxylic acid, carboxylic acid salt, ester, amide , aldehydo, keto, amino, halo, and cyano.
  • R 6 is unsubstituted d-Cio alkyl and R 7 is hydrogen or unsubstituted d-do alkyl.
  • R is unsubstituted C ⁇ C 3 alkyl and R 7 is hydrogen or unsubstituted
  • R is methyl and R 7 is hydrogen.
  • Y Group Generally Y may be any group such that upon reduction of the hypoxic activator the modified anti-neoplastic agent released is cytotoxic or the released modified anti-neoplastic agent undergoes rearrangement, degradation or other chemical transformation to yield a cytotoxic agent.
  • X is the ether group XI and Y is -(CR c R d )- where R c and R d are independently hydrogen, unsubstituted C1-C 3 alkyl, or C ⁇ -C 3 alkyl substituted with one or more of hydroxyl, ether, thiol, thioether, sulfinic ester, sulfoxide, sulfone, sulfonic acid, sulfonic acid ester, sulfenamide, sulfonamide, carboxylic acid, carboxylic acid salt, ester, amide , aldehydo, keto, amino, halo, and cyano; preferably hydroxyl, ether, thiol, thioether, carboxylic acid, carboxylic acid salt, ester, amide , aldehydo, keto, amino, halo, and cyano.
  • X and Y are as described in the prior sentence and Y is attached to the anti- neoplastic agent via the oxygen of a hydroxyl group in the anti-neoplastic agent; i.e., the protected anti-neoplastic agent includes a formacetal group and has the formula Hyp-O- (CH 2 )-O-N', where the anti-neoplastic agent N is N'-OH.
  • X is the ether group XI and Y is -(CH 2 )-.
  • X is the ether group XI, Y is -(CH )-, and Y is attached to the anti-neoplastic agent via the oxygen of a hydroxyl group in the anti-neoplastic agent; i.e., the protected anti-neoplastic agent includes a formacetal group and has the formula Hyp-0-(CH 2 )-O-N', where the anti-neoplastic agent N is N'-OH.
  • X is the acetal group X2 and Y is an unsubstituted C 3 -C 4 alkylene chain or a C 3 -C 4 alkylene chain substituted with one or more heteroatom containing groups.
  • X is the acetal group X2 and Y is an unsubstituted C 3 -C 4 alkylene chain or a C 3 -C 4 alkylene chain substituted with one or more heteroatom containing groups selected from hydroxyl, ether, thiol, thioether, sulfinic ester, sulfoxide, sulfone, sulfonic acid, sulfonic acid ester, sulfenamide, sulfonamide, carboxylic acid, carboxylic acid salt, ester, amide , aldehydo, keto, amino, halo, and cyano; preferably hydroxyl, ether, thiol, thioether, carboxylic acid, carboxylic acid salt, ester, amide , aldehydo, keto, amino, halo, and cyano.
  • X is the acetal group X2
  • Y is as described in any of the previous sentences, and Y is attached to the anti-neoplastic agent via the nitrogen of an amine group in the anti- neoplastic agent; i.e., the protected anti-neoplastic agent includes has the formula Hyp-O- (substituted or unsubstituted C 3 -C 4 alkylene )-NR-N', where the anti-neoplastic agent N is N'-NRR'.
  • X is the acetal group X2 and Y is -(CR e R f )- (CR g R h )-(CH 2 )-, where R e , R f , R g , and R h are independently hydrogen, unsubstituted C ⁇ -C 3 alkyl, or d-C 3 alkyl substituted with one or more of hydroxyl, ether, thiol, thioether, sulfinic ester, sulfoxide, sulfone, sulfonic acid, sulfonic acid ester, sulfenamide, sulfonamide, carboxylic acid, carboxylic acid salt, ester, amide , aldehydo, keto, amino, halo, and cyano; preferably hydroxyl, ether, thiol, thioether, carboxylic acid, carboxylic acid salt, ester, amide
  • R e and R f are independently selected from -H and -O-R 1 , where R 1 is unsubstituted Ci-C 5 alkyl.
  • R ⁇ and R h are independently selected from -H and -O-R 1 , where R 1 is unsubstituted d-C 5 alkyl.
  • X is the acetal group X2
  • Y is as in any of the versions described in the previous sentences in the paragraph, and Y is attached to the anti-neoplastic agent via the nitrogen of an amine group in the anti-neoplastic agent; i.e., the protected anti-neoplastic agent includes has the formula Hyp-0-(substituted or unsubstituted C 3 -C 4 alkylene )-NR-N', where the anti- neoplastic agent N is N'-NRR'.
  • X is the acetal group X2 and Y is -(CR e R f )- (CR g R h )-(CR j R k )-(CH 2 )-, where R 6 , R f , R , R h , R j , and R k are independently hydrogen, unsubstituted C 1 -C 3 alkyl, or d-C 3 alkyl substituted with one or more of hydroxyl, ether, thiol, thioether, sulfinic ester, sulfoxide, sulfone, sulfonic acid, sulfonic acid ester, sulfenamide, sulfonamide, carboxylic acid, carboxylic acid salt, ester, amide , aldehydo, keto, amino, halo, and cyano; preferably hydroxyl, ether, thiol, thio
  • R e and R f are independently selected from -H and -O-R 1 , where R 1 is -H or unsubstituted d-d alkyl.
  • R g and R h are independently selected from -H and -O-R 1 , where R 1 is -H or unsubstituted d-d alkyl.
  • R J and R k are independently selected from -H and -O-R 1 , where R 1 is -H or unsubstituted d-d alkyl.
  • X is the acetal group X2
  • Y is as in any of the versions described in the previous sentences in the paragraph, and Y is attached to the anti-neoplastic agent via the nitrogen of an amine group in the anti-neoplastic agent; i.e., the protected anti-neoplastic agent has the formula Hyp-O-(substituted or unsubstituted C 3 -C alkylene )-NR-N', where the anti-neoplastic agent N is N'-NRR'.
  • R and R are independently selected from C1-C1 0 alkyl or C1-C10 alkyl substituted with one or more heteroatom containing groups, selected from hydroxyl, ether, thiol, thioether, sulfinic ester, sulfoxide, sulfone, sulfonic acid, sulfonic acid ester, sulfenamide, sulfonamide, carboxylic acid, carboxylic acid salt, ester, amide , aldehydo, keto, amino, halo, and cyano; preferably hydroxyl, ether, thiol, thioether, carboxylic acid, carboxylic acid salt, ester, amide , aldehydo, keto, amino, halo, and cyano.
  • Y contains a delayed release group:
  • the Y group is chosen such that the modified anti-neoplastic agent released upon reduction of the hypoxic activator is converted after release into the anti-neoplastic agent or some active derivative of the anti- neoplastic agent.
  • this degradation occurs by a unimolecular degradation with a half life of unimolecular segregation of between about 0.01 seconds and about 30 seconds.
  • this degradation occurs by a unimolecular degradation with a half life of unimolecular segregation of between about 0.5 seconds and about 5 seconds.
  • the anti-neoplastic agent or some active derivative of the anti-neoplastic agent is delivered not only at the site of hypoxic reduction of the protected anti-neoplastic agent, but also in surrounding tissue. This occurs because the modified anti-neoplastic agent released upon reduction of the hypoxic activator has time to diffuse to surrounding tissue before it degrades to release the anti-neoplastic agent or active derivative of the anti-neoplastic agent.
  • Y has the formula - ⁇ io R n R-i2 n -' where R ⁇ is an unsubstituted or substituted aryl or heteroaryl group, Rio is a bond or group attaching the R ⁇ group to the X group in the linker, and R1 2 is a bond or group attaching the R ⁇ group to the anti-neoplastic agent.
  • X is the ether group and Y has the formula ⁇ Rio R11 R ⁇ 2 ' ⁇ ' ⁇ th R 10 , R ⁇ , and R1 2 as described in any of the versions in this section.
  • R ⁇ can be any unsubstituted or substituted aryl or heteroaryl group, and the aryl or heteroaryl group may be a monocyclic group or may be a fused ring system.
  • fused ring systems examples include but are not limited to naphthyl, quinoline or isoquinoline.
  • the aryl or heteroaryl group is not a monocyclic or fused ring 5 membered aromatic ring system.
  • the point of attachment of the aryl or heteroaryl group to the Rio and Ri 2 groups may generally be at any ring atom to which a substituent group may be attached and that will allow elimination of the Rio and R 12 groups.
  • the aryl or heteroaryl group is any group that will allow 1,6 or 1,4 elimination.
  • the substituted aryl or heteroaryl group is substituted with one or more groups selected from an electron withdrawing group, substituted or unsubstituted and substituted or unsubstituted alkoxy.
  • the substituted aryl or heteroaryl group is substituted with one or more groups selected from an electron withdrawing group, unsubstituted d- alkyl, substituted d-d alkyl, unsubstituted C ⁇ -C 6 alkoxy, and substituted C ⁇ -C 6 alkoxy; where the substituted alkyl or alkoxy are substituted with one or more groups selected from ether (-
  • Examples of monocyclic heteroaryl groups that may be used include but are not limited to pyridyl, pyridazinyl, and pyrimidinyl.
  • the point of attachment of the heteroaryl group to the R 10 and Ri 2 groups may generally be at any ring atom to which a substituent group may be attached and that will allow elimination of the Rio and R 12 groups.
  • R ⁇ is an unsubstituted or substituted aryl, particularly an unsubstituted or substituted phenyl.
  • R ⁇ is an unsubstituted or substituted phenyl in which the R 10 and R 12 groups are in ortho or para to each other; i.e., Y has the formula
  • R ⁇ 3 -R 2 o are independently selected from an electron withdrawing group, unsubstituted d-C 6 alkyl, substituted C ⁇ -C 6 alkyl, unsubstituted d-C 6 alkoxy, and substituted C ⁇ -C 6 alkoxy; where the substituted alkyl or alkoxy are substituted with one or more groups selected from ether (-OR 20 ), amino (-NH 2 ), mono-substituted amino (-NR 20 H), di-substituted amino (-NR 21 R 22 ), cyclic C 1-5 alkylamino, imidazolyl, C ⁇ -6 alkylpiperazinyl, morpholino, thiol (-SH), thioether -(SR 20 ), tetrazole, carboxylic acid (-COOH), ester (- COOR 20 ), amide (-CONH 2 ), mono-substituted amide (-CONHR 20 ), disubstit
  • the Rio group is a bond and the Ri i group is attached directly to the X linker group.
  • the X group is the ether XI
  • R ⁇ group is a bond
  • R ⁇ is an unsubstituted or substituted phenyl in which the Rio and R 12 groups are ortho or para to each other; i.e., the linking group L has the formula
  • R1 3 -R 20 are as described in any version above.
  • R12 Group is generally any group capable of linking the aryl or heteroaryl group ⁇ to a protectable group in the anti-neoplastic agent and which will yield the anti- neoplastic agent or a cytotoxic derivative of the anti-neoplastic agent upon degradation of the modified anti-neoplastic agent that was released upon reduction of the hypoxic activator.
  • R 40 and R 41 are hydrogen.
  • the anti-neoplastic agent, N may be any agent capable of being protected using the hypoxic activator and linking groups described above and that generates a cytotoxic anti-neoplastic agent or modified anti-neoplastic agent upon release after reduction of the hypoxic activator.
  • N is a cytotoxic agent having an IC 50 less than 100 microM, and optionally less than 1 microM, as defined by the NCI screening assay as an LC 5 o after a 24 hr drug treatment of a sensitive cell line.
  • the cytotoxic agent has an IC 5 o less than 10 nanomolar.
  • N is doxorubicin.
  • N is doxorubicin linked to the hypoxic activator via a linking group which is such that reduction of the hypoxic activator releases modified doxorubicin having an IC 5 o in the low nanomolar range.
  • N is selected from the group consisting of maytansines, enediyenes, discodermolides, epothilones, taxanes, calicheamicins, and tedanolides.
  • N is selected from the group consisting of etoposide, vinblastine, vincristine, topotecan, 5- fluorouracil, AQ4N, and hydroxyurea.
  • anti-neoplastic agents that can incorporated in or released from the protected anti-neoplastic agents include but are not limited to bleomycins, calicheamicins, colchicine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, discodermolides, doxorubicin and doxorubicin-like compounds such as epirubicin and derivatives, enediyenes, epothilones, etoposide, Combretastatin A-4, fludarabine, 5-fluorouracil or prodrugs thereof such as Xeloda marketed by Roche, hydroxyurea, hydroxyureapentostatin, maytansines, 6- mercaptopurine, methotrexate, mitomycin, mitoxantrone, platinum-containing agents including but not limited to carboplatin and cisplatin, prednisone, procarbazin
  • anti-neoplastic agents that can incorporated in or released from the protected anti-neoplastic agents include but are not limited to anti-angiogenic agents, alkylating agents, antimetabolite, microtubulin polymerization perturbers (for example, Taxol), certain natural products, platinum coordination complexes, anthracenediones, substituted ureas, methylhydrazine derivatives, adrenocortical suppressants, certain hormones and antagonists, anti-cancer polysaccharides and certain herb or other plant extracts.
  • the anti-neoplastic agents that may be protected using the hypoxic activators and linking groups described herein are the class of cytotoxic antibiotics known as anthracyclines.
  • Anthracyclines include but are not limited to Aclarubicin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone, Pirarubicin, and Valrubicin, and any analogs of the foregoing.
  • Anthracycline analogs are well known in the art and are included in the class of anthracyclines that may be protected using the hypoxic activators and linking groups described herein.
  • anti-neoplastic agents that can incorporated in or released from the protected anti-neoplastic agents include analogs of any of the forgoing agents described in this section. With their knowledge of the art and the teachings in this patent, one of skill in the art will understand how to identify and synthesize analogs of the foregoing and how to protect analogs of the foregoing to produce a protected anti-neoplastic agent as described in this patent.
  • the anti-neoplastic agent is attached to the hypoxic activator (Hyp) either directly or through a linking group (L); i.e., the structure of the protected anti-neoplastic agent is Hyp- N or Hyp-L-N.
  • the hypoxic activator or linking group may be attached to any moiety in the anti-neoplastic agent capable of attachment and that provides a prodrug of the anti-neoplastic agent.
  • the hypoxic activator or linking group is attached to a hydroxyl or amine group in the anti-neoplastic agent.
  • the hydrogen on the hydroxyl group and one or more of the substituents on the amine group are replaced with a bond to a moiety in the hypoxic activator or linking group.
  • the anti-neoplastic agent may be attached to the hypoxic activator or linking group through a variety of groups including but not limited to ethers, carbamates, carbonates esters, acetals, amides and amines.
  • the hypoxic activator or linking group is attached to the anti-neoplastic agent through an ether, amine or carbamate.
  • the anti-neoplastic agent N may be represented as N'-Z, where Z is -OH or -NR a R b and N' represents the remainder of the anti-neoplastic agent.
  • R a and R b are such that the - NR a R b is a primary, secondary or tertiary amine group.
  • -NR a R b is any amine type group capable of bonding to the hypoxic activator or linking group by replacement of one or both of R a and R .
  • Z is -NH 2 .
  • Z in -NHR a In one version, Z in -NHR a .
  • Z is a hydroxyl and the hydroxyl is bonded to an aromatic group in the anti-neoplastic agent.
  • the aromatic group to which the hydroxyl is bonded is a phenyl or substituted phenyl.
  • the substituted phenyl may be part of a fused ring system.
  • the anti- neoplastic agent is attached to the hypoxic activator or linking group in one of the following ways
  • the anti- neoplastic agent upon protection by the hypoxic activator or linking group, is attached to the hypoxic activator or linking group via either the ether or the carbamate linker as shown above.
  • nitrogens in the anti-neoplastic agents may be protected using the hypoxic activators and linking groups described in this patent.
  • nitrogen groups that may be protected include but are not limited to amide groups, heterocyclic amines (including but not limited to indoles, imidazoles, and benzimidazoles), and the nitrogen of an isoquinoline.
  • amides in one version the group directly attached to the anti-neoplastic agent nitrogen is not a carbamate.
  • the protected anti-neoplastic agents may be used in methods for treating cancer.
  • an effective amount of a protected anti-neoplastic agent is administered to the subject.
  • the subject may be any human or non-human mammal.
  • the preferred subject is a human subject.
  • Other particular subjects include but are not limited to non- human primates dogs, cats, farm animals, horses,
  • the protected anti- neoplastic agent is administered alone.
  • the protected anti-neoplastic agent is administered in combination with one or more additional anti-cancer agents.
  • the protected anti-neoplastic agent is administered in conjunction with a therapeutic cancer treatment, including but not limited to surgery and radiation.
  • the protected anti-neoplastic agent will typically be administered in a pharmaceutical composition.
  • Various pharmaceutical compositions that may be used are described in the Formulations section of this patent.
  • the protected anti-neoplastic agents and their pharmaceutical compositions can be used to treat any type of cancer in a subject, particularly in a human subject.
  • Cancers that may be treated include but are not limited to leukemia, breast cancer, skin cancer, bone cancer, liver cancer, brain cancer, cancer of the larynx, gallbladder, pancreas, rectum, parathyroid, thyroid, adrenal, neural tissue, head and neck, stomach, bronchi, kidneys, basal cell carcinoma, squamous cell carcinoma of both ulcerating and papillary type, metastatic skin carcinoma, osteosarcoma, Ewing's sarcoma, veticulum cell sarcoma, myeloma, giant cell tumor, small-cell lung tumor, gallstones, islet cell tumor, primary brain tumor, acute and chronic lymphocytic and granulocytic tumors, hairy-cell tumor, adenoma, hyperplasia, medullary carcinoma, pheochromocytoma, mucosal neuro
  • the protected anti-neoplastic agents may particularly be used in the treatment of cancers containing significant areas of hypoxic tissue.
  • cancers include but are not limited to lung cancer, especially non-small cell lung cancer, breast cancer, colon cancer, head and neck cancer, ovarian cancer, pancreatic cancer, and prostate cancer.
  • lung cancer especially non-small cell lung cancer, breast cancer, colon cancer, head and neck cancer, ovarian cancer, pancreatic cancer, and prostate cancer.
  • cancer chemotherapy often involves the simultaneous or successive administration of a variety of anti-cancer agents, and as discussed further below, the protected anti-neoplastic agents can be used in combination therapies as provided by the methods described herein.
  • illustrative combination therapies are also described.
  • Lung cancer affects more than 100,000 males and 50,000 females in the United States, most of whom die within 1 year of diagnosis, making it the leading cause of cancer death.
  • Current protocols for the treatment of lung cancer involve the integration of chemotherapy with or without radiotherapy or surgery.
  • the protected anti-neoplastic agents including those that release chemotherapeutic agents presently used to treat various forms of lung cancer, can be used to treat lung cancer, for example, by replacing a non-hypoxia- activated form in the combination, and other protected anti-neoplastic agents can be used in existing combination therapies.
  • combination chemotherapy regimens have been reported for small cell lung cancer, including the combinations consisting of cyclophosphamide, doxorubicin and vincristine (CAV); etoposide and cisplatin (VP-16); and cyclophosphamide, doxorubicin and VP-16 (CAVP-16).
  • CAV doxorubicin and vincristine
  • VP-16 etoposide and cisplatin
  • CAVP-16 cyclophosphamide, doxorubicin and VP-16
  • Modest survival benefits from combination chemotherapy (etoposide plus cisplatin) treatment have been reported for non- small cell lung cancer.
  • the protected anti-neoplastic agents described in this patent may be based on each of the chemotherapeutic agents listed above.
  • cytotoxic drugs have produced at least temporary regression of ovarian cancer.
  • the most active drugs in the treatment of ovarian have been alkylating agents, including cyclophosphamide, ifosfamide, melphalan, chlorambucil, thiotepa, cisplatin, and carboplatin.
  • Current combination therapies for ovarian cancer includes cisplatin or carboplatin in combination with cyclophosphamide at 3- to 4-week intervals for six to eight cycles.
  • the compounds and methods described herein provide prodrug forms of each of these agents, and methods for treating ovarian cancer in which a protected anti- neoplastic agent as described herein is used in such combinations, either to replace an agent or in addition to the agent(s) currently used.
  • Cancer of the prostate is the most common malignancy in men in the United States and is the second most common cause of cancer death in men above age 55, and this cancer has been reported to consist primarily of hypoxic tissue.
  • Agents for the treatment of prostate cancer include estramustine phosphate, prednimustine, and cisplatin, and prodrug forms of each of these agents is provided by the compounds and methods described herein, as well as methods for treating prostate cancer using such agents.
  • Combination chemotherapy is also used to treat prostate cancer, including treatment with estramustine phosphate plus prednimustine and cisplatin, and 5-fluorouracil, melphalan, and hydroxyurea.
  • the compounds and methods described herein provide prodrug forms of each of these agents, and methods for treating prostate cancer in which a protected anti-neoplastic agent is used in such combinations, either to replace an agent or in addition to the agent(s) currently used.
  • the protected anti-neoplastic agents may be used in various known approaches to cancer therapy including but not limited to "anti-body- directed enzyme prodrug therapy” (ADEPT), “virus-directed enzyme prodrug therapy (VDEPT), “gene-directed enzyme prodrug therapy” (GDEPT), and “bacteria-directed enzyme prodrug therapy” (BDEPT).
  • ADPT anti-body- directed enzyme prodrug therapy
  • VDEPT virus-directed enzyme prodrug therapy
  • GDEPT gene-directed enzyme prodrug therapy
  • BDEPT Bacia-directed enzyme prodrug therapy
  • the general uses of the protected anti-neoplastic agents are not limited to the foregoing treatment methods.
  • the protected anti-neoplastic agents will typically be formulated as pharmaceutical formulations for administration to a subject. Described in this section are modes of administration, formulations, and dosages that may be used when treating cancers using the protected anti-neoplastic agents described in this patent.
  • Administration of the protected anti-neoplastic agents for the treatment of cancer can be effected by any method that enables delivery of the prodrugs to the site of action, the hypoxic region of a tumor.
  • Many cancer drugs are administered by intravenous injection, and the protected anti-neoplastic agent may be formulated for such administration, including not only ready-for-injection formulations but also lyophilized or concentrated formulations that must be rehydrated or diluted, respectively, prior to injection.
  • the protected anti-neoplastic agent may be formulated for administration by oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal routes.
  • the protected anti-neoplastic agent can be activated by bacteria in the gut. If such activation is not desired, then the practitioner may employ a route of administration or a formulation that results in absorption of the protected anti-neoplastic agent prior to its entry into the large intestine or colon.
  • the actual route of admimstration and corresponding formulation of the protected anti-neoplastic agents will depend on the type of cancer being treated, the protected anti-neoplastic agent selected for administration, the severity of the cancer, and the age, weight, and condition of the patient, among other factors.
  • an effective dosage is typically in the range of about 0.001 to about 100 mg per kg body weight, preferably about 1 to about 35 mg/kg/day, in single or divided doses.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect; larger doses can also be divided into several small doses for administration throughout the day.
  • a formulation of a protected anti-neoplastic agent may, for example, be in a form suitable for oral administration as a tablet, capsule, pill powder, sustained release formulation, solution, and suspension; for parenteral injection as a sterile solution, suspension or emulsion; for topical administration as an ointment or cream; and for rectal admimstration as a suppository.
  • a formulation of a protected anti-neoplastic agent may be in unit dosage forms suitable for single administration of precise dosages and will typically include a conventional pharmaceutical carrier or excipient.
  • Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents.
  • the pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients, and the like.
  • excipients such as citric acid
  • disintegrants such as starch, alginic acid, and certain complex silicates
  • binding agents such as sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate, and talc can be used to prepare the tablet forms of formulations of the protected anti-neoplastic agents described herein.
  • Solid compositions of a similar type can be employed in soft and hard filled gelatin capsules.
  • Preferred materials include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the prodrug therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
  • Exemplary parenteral administration forms include solutions or suspensions of the hypoxia-activated prodrug in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
  • Methods of preparing various pharmaceutical compositions with a specific amount of active drug are known, or will be apparent, to those skilled in this art in view of this disclosure. For examples, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 17 th Edition (1984).
  • the protected anti-neoplastic agents described in this patent may be made by a variety of methods. Given the synthesis methods described in the examples below and their knowledge of synthetic medicinal chemistry, one of skill in the art will be able to synthesize the protected anti-neoplastic agents in a straightforward manner.
  • a protected anti-neoplastic agent is administered in combination with an effective amount of one or more chemotherapeutic agents, an effective amount of radiotherapy, an appropriate surgery procedure, or any combination of such additional therapies.
  • the protected anti-neoplastic agent and additional therapy may be administered at the same time or may be administered separately.
  • the two agents may be administered simultaneously or may be administered sequentially with some time between administrations.
  • One of skill in the art will understand methods of administering the agents simultaneously and sequentially and possible time periods between administration.
  • the agents may be administered as the same or different formulations and may be administered via the same or different routes.
  • Chemotherapeutic agents that may be used in combination with the protected anti- neoplastic agents described in this patent include but are not limited to busulfan, improsulfan, piposulfan, benzodepa, carboquone, 2-deoxy-D-glucose, lonidamine, meturedepa, uredepa, altretamine, imatinib, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylolomelamine, chlorambucil, chlornaphazine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, nimustine, ranimustine, dacarbazine, mannomustine, mitobronitol,
  • chemotherapeutic agents that may be used include platinum derivatives, including but not limited to cis platinum, carboplatin, and oxoplatin.
  • the protected anti-neoplastic agents described in this patent may be used in combination with an antiangeogenisis inhibitor including but not limited to Avastin and similar therapeutics.
  • a subject is treated with an antiangeogenisis inhibitor and subsequently treated with a protected anti- neoplastic agent.
  • a subject is treated with an antiangeogenisis inhibitor and subsequently treated with a protected anti-neoplastic agent with another chemotherapeutic agent, including but not limited to Cis platinum.
  • the method is used to treat breast cancer.
  • a protected anti-neoplastic agent is administered with an anticancer agent that acts, either directly or indirectly, to inhibit hypoxia-inducible factor 1 alpha (HIFla) or to inhibit a protein or enzyme, such as a glucose transporter or VEGF, whose expression or activity is increased upon increased HIFla levels.
  • an anticancer agent that acts, either directly or indirectly, to inhibit hypoxia-inducible factor 1 alpha (HIFla) or to inhibit a protein or enzyme, such as a glucose transporter or VEGF, whose expression or activity is increased upon increased HIFla levels.
  • HIFla inhibitors suitable for use in this version of the methods and compositions described herein include PI 3 kinase inhibitors; LY294002; rapamycin; histone deacetylase inhibitors such as [(E)- (lS,4S,10S,21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23- tetraazabicyclo-[8,7,6]-tricos-16-ene-3,6,9,19,22-pentanone (FR901228, depsipeptide); heat shock protein 90 (Hsp90) inhibitors such as geldanamycin, 17-allylamino-geldanamycin (17- AAG), and other geldanamycin analogs, and radicicol and radicicol derivatives such as KF58333; genistein; indanone; staurosporin; protein kinase- 1
  • a protected anti-neoplastic agent is administered with an anti- angiogenic agent, including but not limited to anti-angiogenic agents selected from the group consisting of angiostatin, an agent that inhibits or otherwise antagonizes the action of VEGF, batimastat, captopril, cartilage derived inhibitor, genistein, endostatin, interleukin, lavendustin A, medroxypregesterone acetate, recombinant human platelet factor 4, Taxol, tecogalan, thalidomide, thrombospondin, TNP-470, and Avastin.
  • angiostatin an agent that inhibits or otherwise antagonizes the action of VEGF
  • batimastat captopril
  • cartilage derived inhibitor genistein
  • endostatin interleukin
  • lavendustin A lavendustin A
  • medroxypregesterone acetate recombinant human platelet factor 4
  • Taxol
  • angiogenesis inhibitors for purposes of the combination therapies provided by the present methods and compositions described herein include Cox-2 inhibitors like celecoxib (Celebrex), diclofenac (Voltaren), etodolac (Lodine), fenoprofen (Nalfon), indomethacin (Indocin), ketoprofen (Orudis, Oruvail), ketoralac (Toradol), oxaprozin (Daypro), nabumetone (Relafen), sulindac (Clinoril), tolmetin (Tolectin), rofecoxib (Vioxx), ibuprofen (Advil), naproxen (Aleve, Naprosyn), aspirin, and acetaminophen (Tylenol).
  • Cox-2 inhibitors like celecoxib (Celebrex), diclofenac (Voltaren), etodolac (Lodine), fenoprofen
  • pyruvate mimics and glycolytic inhibitors like halopyruvates, including bromopyruvate can be used in combination with an anti-angiogenic compound and a protected anti-neoplastic agent to treat cancer.
  • a protected anti- neoplastic agent is administered with an anti-angiogenic agent and another anti-cancer agent, including but not limited to a cytotoxic agent selected from the group consisting of alkylators, Cisplatin, Carboplatin, and inhibitors of microtubule assembly, to treat cancer.
  • the present methods and compositions described herein provides a variety of synergistic combinations of a protected anti-neoplastic agent and other anti-cancer drugs. Those of skill in the art can readily determine the anti-cancer drugs that act "synergistically" with a protected anti-neoplastic agent as described herein.
  • Two drugs can be said to possess therapeutic synergy if a combination dose regimen of the two drugs produces a significantly better tumor cell kill than the sum of the single agents at optimal or maximum tolerated doses.
  • the "degree of synergy" can be defined as net log of tumor cell kill by the optimum combination regimen minus net log of tumor cell kill by the optimal dose of the most active single agent. Differences in cell kill of greater than ten-fold (one log) are considered conclusively indicative of therapeutic synergy.
  • a protected anti-neoplastic agent When a protected anti-neoplastic agent is used with another anti-cancer agent, a protected anti-neoplastic agent will, at least in some versions, be administered prior to the initiation of therapy with the other drug or drugs and administration will typically be continued throughout the course of treatment with the other drug or drugs. In some versions, the drug co-administered with a protected anti-neoplastic agent will be delivered at a lower dose, and optionally for longer periods, than would be the case in the absence of a protected anti-neoplastic agent administration.
  • Such "low dose” therapies can involve, for example, administering an anti-cancer drug, including but not limited to paclitaxel, docetaxel, doxorubicin, cisplatin, or carboplatin, at a lower than approved dose and for a longer period of time together with a protected anti-neoplastic agent administered in accordance with the methods described herein.
  • an anti-cancer drug including but not limited to paclitaxel, docetaxel, doxorubicin, cisplatin, or carboplatin.
  • the additional anti-cancer agent(s) when employed in combination with a protected anti-neoplastic agent, are dosed using either the standard dosages employed for those agents when used without a protected anti- neoplastic agent or are less than those standard dosages.
  • the administration of a protected anti-neoplastic agent in accordance with the methods described herein can therefore allow the physician to treat cancer with existing (or later approved) drugs at lower doses (than currently used), thus ameliorating some or all of the toxic side effects of such drugs.
  • Cancer drugs can be classified generally as alkylators, anthracyclines, antibiotics, aromatase inhibitors, bisphosphonates, cyclo-oxygenase inhibitors, estrogen receptor modulators, folate antagonists, inorganic aresenates, microtubule inhibitors, modifiers, nitrosoureas, nucleoside analogs, osteoclast inhibitors, platinum containing compounds, retinoids, topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, and tyrosine kinase inhibitors.
  • a protected anti-neoplastic agent can be co-administered with any anti-cancer drug from any of these classes or can be administered prior to or after treatment with any such drug or combination of such drugs.
  • a protected anti-neoplastic agent can be administered in combination with a biologic therapy (e.g., treatment with interferons, interleukins, colony stimulating factors and monoclonal antibodies).
  • Biologies used for treatment of cancer are known in the art and include, for example, frastuzumab (Herceptin), tositumomab and 131 I Tositumomab (Bexxar), rituximab (Rituxan).
  • the anti-cancer drug co-administered with a protected anti-neoplastic agent is not a topoisomerase inhibitor.
  • Alkylators useful in the practice of the methods described herein include but are not limited to busulfan (Myleran, Busulfex), chlorambucil (Leukeran), ifosfamide (with or without MESNA), cyclophosphamide (Cytoxan, Neosar), glufosfamide, melphalan, L-PAM (Alkeran), dacarbazine (DTIC-Dome), and temozolamide (Temodar).
  • busulfan Myleran, Busulfex
  • chlorambucil Leukeran
  • ifosfamide with or without MESNA
  • cyclophosphamide Cytoxan, Neosar
  • glufosfamide glufosfamide
  • melphalan L-PAM (Alkeran)
  • DTIC-Dome dacarbazine
  • Temodar temozolamide
  • the cancer is chronic myelogenous leukemia, multiple myeloma, or anaplastic astrocytoma.
  • the compound 2-bis[(2- chloroethyl)amino] tetra-hydro-2H-l,3,2-oxazaphosphorine, 2-oxide, also commonly known as cyclophosphamide is an alkylator used in the treatment of Stages III and IV malignant lymphomas, multiple myeloma, leukemia, mycosis fungoides, neuroblastoma, ovarian adenocarcinoma, retinoblastoma, and carcinoma of the breast.
  • Cyclophosphamide is administered for induction therapy in doses of 1500-1800 mg/m 2 that are administered intravenously in divided doses over a period of three to five days; for maintenance therapy,
  • a protected anti-neoplastic agent is co-administered with cyclosphosphamide administered at such doses or at lower doses and/or for a longer duration than normal for administration of cyclosphosphamide alone.
  • Anthracyclines useful in the practice of the methods described herein include but are not limited to doxorubicin (Adriamycin, Doxil, Rubex), mitoxantrone (Novantrone), idarubicin (Idamycin), valrubicin (Valstar), and epirubicin (Ellence).
  • doxorubicin Adriamycin, Doxil, Rubex
  • mitoxantrone Novantrone
  • idarubicin Idamycin
  • valrubicin valrubicin
  • Ellence epirubicin
  • a protected anti-neoplastic agent is co-administered with an anthracycline to treat cancer.
  • the cancer is acute nonlymphocytic leukemia, Kaposi's sarcoma, prostate cancer, bladder cancer, metastatic carcinoma of the ovary, and breast cancer.
  • the compound (8S,10S)-10-[(3-Amino-2,3,6-trideoxy-.alpha.- L-lyxo-hexopyranosyl)oxy]-8-glycoloyl-7,8,9, 10-tetrahydro-6,8, 11 -trihydroxy-1 -methoxy- 5,12-naphthacenedione, more commonly known as doxorubicin, is a cytotoxic anthracycline antibiotic isolated from cultures of Streptomyces peucetius var. caesius.
  • Doxorubicin has been used successfully to produce regression in disseminated neoplastic conditions such as acute lymphoblastic leukemia, acute myeloblastic leukemia, Wilm's tumor, neuroblastoma, soft tissue and bone sarcomas, breast carcinoma, ovarian carcinoma, transitional cell bladder carcinoma, thyroid carcinoma, lymphomas of both Hodgkin and non-Hodgkin types, bronchogenic carcinoma, and gastric carcinoma.
  • Doxorubicin is typically administered in a dose in the range of 30-75 mg/m 2 as a single intravenous injection administered at 21 -day
  • a protected anti-neoplastic agent is co-administered starting prior to and continuing after the administration of doxorubicin at such doses (or at lower doses).
  • Antibiotics useful in the practice of the methods described herein include but are not limited to dactinomycin, actinomycin D (Cosmegen), bleomycin (Blenoxane), daunorubicin, and daunomycin (Cerubidine, DanuoXome).
  • a protected anti-neoplastic agent is co-administered with an antibiotic to treat cancer.
  • the cancer is a cancer selected from the group consisting of acute lymphocytic leukemia, other leukemias, and Kaposi's sarcoma.
  • Aromatase inhibitors useful in the practice of the methods described herein include but are not limited to anastrozole (Arimidex) and letroazole (Femara). In accordance with the methods described herein a protected anti-neoplastic agent is co-administered with an aromatase inhibitor to treat cancer. In one version, the cancer is breast cancer.
  • Bisphosphonate inhibitors useful in the practice of the methods described herein include but are not limited to zoledronate (Zometa). In accordance with the methods described herein a protected anti-neoplastic agent is co-administered with a biphosphonate inhibitor to treat cancer.
  • the cancer is a cancer selected from the group consisting of multiple myeloma, bone metastases from solid tumors, or prostate cancer.
  • Cyclo-oxygenase inhibitors useful in the practice of the methods described herein include but are not limited to celecoxib (Celebrex).
  • a protected anti-neoplastic agent is co-administered with a cyclo-oxygenase inhibitor to treat cancer.
  • the cancer is colon cancer or a pre-cancerous condition known as familial adenomatous polyposis.
  • Estrogen receptor modulators useful in the practice of the methods described herein include but are not limited to tamoxifen (Nolvadex) and fulvestrant (Faslodex).
  • a protected anti-neoplastic agent is co-administered with an estrogen receptor modulator to treat cancer.
  • the cancer is breast cancer or the treatment is administered to prevent the occurrence or reoccurrence of breast cancer.
  • Folate antagonists useful in the practice of the methods described herein include but are not limited to methotrexate and tremetrexate.
  • a protected anti-neoplastic agent is co-administered with a folate antagonist to treat cancer.
  • the cancer is osteosarcoma.
  • the compound N-[4- [[(2,4-diamino-6-pteridinyl)methyl methylamino]benzoyl]-L-glutamic acid commonly known as methotrexate
  • methotrexate is an antifolate drug that has been used in the treatment of gestational choriocarcinoma and in the treatment of patients with chorioadenoma destruens and hydatiform mole. It is also useful in the treatment of advanced stages of malignant lymphoma and in the treatment of advanced cases of mycosis fungoides.
  • Methotrexate is administered as follows.
  • intramuscular injections of doses of 15 to 30 mg are administered daily for a five-day course, such courses repeated as needed with rest period of one or more weeks interposed between courses of therapy.
  • twice weekly intramuscular injections are administered in doses of 30 mg/m 2 .
  • weekly intramuscular injections of doses of 50 mg or, alternatively, of 25 mg are administered twice weekly.
  • a protected anti-neoplastic agent is co-administered with methotrexate administered at such doses (or at lower doses).
  • 5-Methyl-6-[[(3,4,5-trimethoxyphenyl)-amino]methyl]-2,4-quinazolinediamine (commonly known as trimetrexate) is another antifolate drug that can be co-administered with a protected anti-neoplastic agent.
  • Inorganic arsenates useful in the practice of the methods described herein include but are not limited to arsenic trioxide (Trisenox).
  • Trisenox arsenic trioxide
  • a protected anti-neoplastic agent is co-administered with an inorganic arsenate to treat cancer.
  • the cancer is refractory acute promyelocytic leukemia (APL).
  • Microtubule inhibitors (as used herein, a "microtubule inhibitor” is any agent that interferes with the assembly or disassembly of microtubules) useful in the practice of the methods described herein include but are not limited to vincristine (Oncovin), vinblastine (Velban), paclitaxel (Taxol, Paxene), vinorelbine (Navelbine), docetaxel (Taxotere), epothilone B or D or a derivative of either, and discodermolide or its derivatives.
  • a protected anti-neoplastic agent is co- administered with a microtubule inhibitor to treat cancer.
  • the cancer is ovarian cancer, breast cancer, non-small cell lung cancer, Kaposi's sarcoma, and metastatic cancer of breast or ovary origin.
  • the compound 22-oxo-vincaleukoblastine also commonly known as vincristine, is an alkaloid obtained from the common periwinkle plant (Vinca rosea, Linn.) and is useful in the treatment of acute leukemia. It has also been shown to be useful in combination with other oncolytic agents in the treatment of Hodgkin's disease, lymphosarcoma, reticulum-cell sarcoma, rhabdomyosarcoma, neuroblastoma, and Wilm's tumor.
  • Vincristine is administered in weekly intravenous doses of 2 mg/m 2 for children and 1.4 mg/m 2 for adults.
  • a protected anti- neoplastic agent is co-administered with vincristine administered at such doses.
  • a protected anti-neoplastic agent is not administered prior to treatment with a microtubule inhibitor, such as a taxane, but rather, administration of a protected anti- neoplastic agent is administered simultaneously with or within a few days to a week after initiation of treatment with a microtubule inhibitor.
  • Modifiers useful in the practice of the methods described herein include but are not limited to Leucovorin (Wellcovorin), which is used with other drugs such as 5-fluorouracil to treat colorectal cancer.
  • a protected anti- neoplastic agent is co-administered with a modifier and another anti-cancer agent to treat cancer.
  • the cancer is colon cancer.
  • the modifier is a compound that increases the ability of a cell to take up glucose, including but not limited to the compound N-hydroxyurea.
  • N-hydroxyurea has been reported to enhance the ability of a cell to take up 2-deoxyglucose (see the reference Smith et al., 1999, Cancer Letters 141: 85, incorporated herein by reference), and administration of N-hydroxyurea at levels reported to increase a protected anti-neoplastic agent uptake or to treat leukemia together with administration of a protected anti-neoplastic agent as described herein is one version of the therapeutic methods provided herein.
  • a protected anti-neoplastic agent is co-administered with nitric oxide or a nitric oxide precursor, such as an organic nitrite or a spermineNONOate, to treat cancer, as the latter compounds stimulate the uptake of glucose and so stimulate the uptake of a protected anti-neoplastic agent.
  • Nitrosoureas useful in the practice of the methods described herein include but are not limited to procarbazine (Matulane), lomustine, CCNU (CeeBU), carmustine (BCNU, BiCNU, Gliadel Wafer), and estramustine (Emcyt).
  • a protected anti-neoplastic agent is co-administered with a nitrosourea to treat cancer.
  • the cancer is prostate cancer or glioblastoma, including recurrent glioblastoma multiforme.
  • Nucleoside analogs useful in the practice of the methods described herein include but are not limited to mercaptopurine, 6-MP (Purinethol), fluorouracil, 5-FU (Adrucil), thioguanine, 6-TG (Thioguanine), hydroxyurea (Hydrea), cytarabine (Cytosar-U, DepoCyt), floxuridine (FUDR), fludarabine (Fludara), pentostatin (Nipent), cladribine (Leustatin, 2- CdA), gemcitabine (Gemzar), and capecitabine (Xeloda).
  • a protected anti-neoplastic agent is co-administered with a nucleoside analog to treat cancer.
  • the cancer is B-cell lymphocytic leukemia (CLL), hairy cell leukemia, adenocarcinoma of the pancreas, metastatic breast cancer, non-small cell lung cancer, or metastatic colorectal carcinoma.
  • CLL B-cell lymphocytic leukemia
  • hairy cell leukemia adenocarcinoma of the pancreas
  • metastatic breast cancer metastatic breast cancer
  • non-small cell lung cancer or metastatic colorectal carcinoma.
  • the compound 5-fluoro- 2,4(1 H,3H)-pyrimidinedione also commonly known as 5-fluorouracil
  • 5-fluorouracil is an antimetabolite nucleoside analog effective in the palliative management of carcinoma of the colon, rectum, breast, stomach, and pancreas in patients who are considered incurable by surgical or other means.
  • 5-Fluorouracil is administered in initial therapy in doses of 12 mg/m 2 given intravenously once daily for 4 successive days with the daily dose not exceeding 800 mg. If no toxicity is observed at any time during the course of the therapy, 6 mg/kg are given intravenously on the 6th, 8th, 10th, and 12th days. No therapy is given on the 5th, 7th, 9th, or 11th days.
  • a daily dose of 6 mg/kg is administered for three days, with the daily dose not exceeding 400 mg. If no toxicity is observed at any time during the treatment, 3 mg/kg may be given on the 5th, 7th, and 9th days. No therapy is given on the 4th, 6th, or 8th days. A sequence of injections on either schedule constitutes a course of therapy.
  • a protected anti-neoplastic agent is co-administered with 5-FU administered at such doses or with the prodrug form Xeloda with correspondingly adjusted doses.
  • the compound 2-amino-l,7-dihydro-6H-purine-6-thione is a nucleoside analog effective in the therapy of acute non-pymphocytic leukemias.
  • 6-Thioguanine is orally administered in doses of about 2 mg/kg of body weight per day. The total daily dose may be given at one time. If after four weeks of dosage at this level there is no improvement, the dosage may be cautiously increased to 3 mg/kg/day.
  • a protected anti-neoplastic agent is co- administered with 6-TG administered at such doses (or at lower doses).
  • Osteoclast inhibitors useful in the practice of the methods described herein include but are not limited to pamidronate (Aredia).
  • a protected anti-neoplastic agent is co-administered with an osteoclast inhibitor to treat cancer.
  • the cancer is osteolytic bone metastases of breast cancer, and one or more additional anti-cancer agents are also co-administered with a protected anti-neoplastic agent.
  • Platinum compounds useful in the practice of the methods described herein include but are not limited to cisplatin (Platinol) and carboplatin (Paraplatin).
  • a protected anti-neoplastic agent is co-administered with a platinum compound to treat cancer.
  • the cancer is metastatic testicular cancer, metastatic ovarian cancer, ovarian carcinoma, and transitional cell bladder cancer.
  • the compound cis-Diaminedichloroplatinum (II) commonly known as cisplatin, is useful in the palliative treatment of metastatic testicular and ovarian tumors, and for the treatment of transitional cell bladder cancer which is not amenable to surgery or radiotherapy.
  • Cisplatin when used for advanced bladder cancer, is administered in intravenous injections of doses of 50-70 mg/m once every three to four weeks.
  • a protected anti-neoplastic agent is co-administered with cisplatin administered at these doses (or at lower doses).
  • One or more additional anti-cancer agents can be co- administered with the platinum compound and a protected anti-neoplastic agent.
  • Platinol, Blenoxane, and Velbam may be co-administered with a protected anti- neoplastic agent.
  • Platinol and Adriamycin may be co-administered with a protected anti-neoplastic agent.
  • Retinoids useful in the practice of the methods described herein include but are not limited to tretinoin, ATRA (Vesanoid), alitretinoin (Panretin), and bexarotene (Targretin).
  • a protected anti-neoplastic agent is co- administered with a retinoid to treat cancer.
  • the cancer is a cancer selected from the group consisting of APL, Kaposi's sarcoma, and T-cell lymphoma.
  • Topoisomerase 1 inhibitors useful in the practice of the methods described herein include but are not limited to topotecan (Hycamtin) and irinotecan (Camptostar).
  • a protected anti-neoplastic agent is co- administered with a topoisomerase 1 inhibitor to treat cancer.
  • the cancer is metastatic carcinoma of the ovary, colon, or rectum, or small cell lung cancer.
  • administration of a protected anti-neoplastic agent either precedes or follows, or both, administration of a topoisomerase 1 inhibitor but is not administered concurrently therewith.
  • Topoisomerase 2 inhibitors useful in the practice of the methods described herein include but are not limited to etoposide, VP-16 (Vepesid), teniposide, VM-26 (Vumon), and etoposide phosphate (Etopophos).
  • a protected anti-neoplastic agent is co-administered with a topoisomerase 2 inhibitor to treat cancer.
  • the cancer is a cancer selected from the group consisting of refractory testicular tumors, refractory acute lymphoblastic leukemia (ALL), and small cell lung cancer.
  • Tyrosine kinase inhibitors useful in the practice of the methods described herein include but are not limited to imatinib (Gleevec).
  • a protected anti-neoplastic agent is co-administered with a tyrosine kinase inhibitor to treat cancer.
  • the cancer is CML or a metastatic or unresectable malignant gastrointestinal stromal tumor.
  • a protected anti- neoplastic agent or a pharmaceutically acceptable salt thereof and one or more additional anti-cancer agents are administered to a patient.
  • additional anti-cancer agents include without limitation 5-methyl-6-[[(3,4,5-trimethoxyphenyl)amino]-methyl]-2,4- quinazolinediamine or a pharmaceutically acceptable salt thereof, (8S,10S)-10-(3-amino- 2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-8-glycoloyl-7,8,9, 10-tetrahydro-6,8, 11- trihydroxy-l-methoxy-5,12-naphthacenedione or a pharmaceutically acceptable salt thereof; 5-fluoro-2,4(lH,3H)-pyrimidinedione or a pharmaceutically acceptable salt thereof; 2-amino- l,7-dihydro-6
  • nitroimidazole primary alcohol 3-Methyl-2-nitro-3H-imidazol-4- yl)-methanol is an example of what is refered to in this patent as a "nitroimidazole primary alcohol.” Because protected anti-neoplastic agents containing this hypoxic activator may in some cells be activated even under normoxic conditions due to the attack on the primary carbon of the alcohol by glutathione-S-transferase or via a similar mechanism, and because further substitution of this carbon may reduce or eliminate such unwanted activation, also described in this patent are secondary alcohol versions which are referred to as "the nitroimidazole secondary alcohols". Synthesis of such nitroimidazole secondary alcohols is presented in part B of this example.
  • Part A Synthesis of a Nitroimidazole Primary Alcohol.
  • the following scheme provides a method for the synthesis of the nitroimidazole primary alcohol (compound 2 in the scheme) from ethyl sarcosine.
  • ethylsarcosine hydrochloride is first converted to ethyl-N-formyl-C-formyl sarcosine hydrochloride; a suitable method for such conversion is described in the reference Jones, 1949, J. Am. Chem. Soc. 71: 6AA, incorporated herein by reference.
  • the nitroimidazole ester (compound 1 in the scheme); a suitable method for such conversion is described in the reference Asato et al., 1972, J. Med. Chem. 15: 1086, incorporated herein by reference. Then, the nitroimidazole ester is converted to the nitroimidazole primary alcohol; a suitable method for such conversion is described in Parveen et al., 1999, Bioorg. Med. Chem. Lett. 9: 2031, incorporated herein by reference.
  • nitroimidazole moiety bearing a methyl group at the 1 position.
  • This methyl group can alternatively be an alkyl group bearing steric hinderance or other groups as described in this patent.
  • Such analogs would be useful in reducing the reactivity of the 2 nitro group toward two electron reduction in vivo by oxygen insensitive enzymes such as DT diaphorase.
  • Such hindered analogs can be synthesized by using the scheme above and substituting the N methylglycine ester with a hindered N alkyl glycine ester such as N neopentyl glycine ester.
  • Other hindered groups can be envisioned including but not limited to t-butyl, cyclohexyl, cyclopentyl, isopropyl or any heteroatom substituted variant.
  • either the nitroimidazole ester (compound 1 in the scheme in part A and in the schemes below) or the nitroimidazole primary alcohol (compound 2 in the scheme in part A and in the schemes below) is converted to the nitroimidazole secondary alcohol using either Cerium reagents (second scheme below; see Takeda et al., Organic Syntheses, Volume 76, page 228 et seq. and the references cited therein, incorporated herein by reference) or Titanium reagents (first and third schemes below (see Imwinkelried et al. Organic Syntheses, Volume CV8, page 495 et seq., and the references cited therein, incorporated herein by reference).
  • Etoposide [0215] The following is a prophetic example of an anti-neoplastic agent containing a phenolic group.
  • the etoposide antitumor drug can be specifically alkylated at its phenolic position using the l-methyl-2-nitro-5-bromomethyl-imidazole reagent described in Example 1 under mild condition of a moderate base such as potassium carbonate in an anhydrous solvent such as DMF.
  • a moderate base such as potassium carbonate
  • an anhydrous solvent such as DMF.
  • the above alkylation can be effected under Mitsunobu conditions between the methyl-2-nitro-5-hydrox5 ⁇ ethyl-imidazole and etoposide using triphenyl phosphine and isopropyl azodicarboxylate in DMF.
  • An analogous reaction and experimentals are provided in Toki, etal., Journal of Organic Chemistry, 2002, 67, 1866- 1872 in Example 1. The following structural formula presents a nonlimiting example of such a structure.
  • a nitroimidazole alkyl phenolic ether bearing a para or ortho benzyl alcohol can be used to form a ether connection with the phenolic group of etoposide analogous to the description above.
  • a nitroimidazole alkyl phenolic ether bearing a para or ortho benzyl alcohol can be coupled to form an ether to the phenol of etoposide by first converting the benzyl alcohol to a bromide and then reacting under the standard alkylating conditions described above to effect the desired ether linkage with etoposide.
  • the Mitsunobu conditions described above can be applied to form the desired ether.
  • the following structural formula presents a nonlimiting example of such a structure.
  • Example 3 Combretastatin A-4 and analogs
  • Combretastatin A-4 is a potent inhibitor of microtubules and possesses a single phenolic group that is thought to be essential for compound cytotoxic activity.
  • Combretastatin A-4 analog which differs only by the substitution of the phenolic group with an amino group and is incrementally more potent than Combretastatin A-4. Both of these compounds be modified and rendered inactive and then hypoxically released using the protected anti-neoplastic agents described in this patent.
  • the following protecting groups may be used to protect the hydroxyl or amine groups in the Combretastatin A-4 and analogs, where the * indicates the point of attachment.
  • connection of the third nitroimidazole construct to the parent Combretastatin A- 4 is less optimum as the resulting carbonate may be unstable in vivo due to general esterases.
  • the starting Combretastatin A-4 is commercially available.
  • the amino analog can be synthesized as reported in Ohsumi, K, J. Med. Chem., 41 (16), 3022 -3032, 1998. Synthesis of other analog can be found in the references described in Nam, N, Current Medicinal Chemistry, 2003, 10, 1697-1722.
  • the hypoxically activated technology described in this patent can also be applied to the Duocarmycin family.
  • a simple alkyl connection is described elsewhere in this patent and may be straightforwardly synthesized by methods described above for etoposide.
  • the lower linker connection to the phenol of a duocarmycin may be straightforwardly synthesized as described above for etoposide.
  • Many Duocarmycin analogs have been synthesized and one of skill in the art will understand that the free phenol in the position denoted as O-R may be protected using the protected anti-neoplastic agent technology described in this patent, (see references for analog options: Denny, W,A, Current Medicinal Chemistry, 2001, 533-44 and Searcey, M, Current Pharm. Discovery, 2002, 8, 1375-89.)
  • X may be a variety of groups, including but not limited to halo and sulfonolate, and particularly -Cl.
  • hypoxically activated prodrugs shown can be straightforwardly synthesized where the asterisk is the connection to the phenol or amine of the Duocarmycin,.
  • Barminomycin is a natural product related to daunorubicin. It serves as a pre activated alkylating analog of daunorubicin by bearing an hemiaminal functionality which is in equilibrium upon elimination of water to form the active imine (Moufarij, M.A., et. al.,
  • Barminomycin may be regiospecifically modified on the nitrogen of the hemiaminal function with the nitrophenyl carbonate derived from l-methyl-2-nitro-5-hydroxymethyl imidazole to produce the product shown above where the Ri is shown below (left hand structure) with the asterisk being the connection to the nitrogen.
  • the nitrogen of the hemiaminal of barminomycin can be reacted with the nitrophenyl carbonates of the nitroimidazole alkyl phenolic ether bearing a para or ortho benzyl alcohol as describe previously to produce the barminomycin analog where and example of RI is shown below (right hand structure) with the asterisk being the connection to the nitrogen.
  • Example 6 Anthramycin and related analogs [0230] The following is a prophetic example of an anti-neoplastic agent containing a hemiaminal group.
  • Coli nitroreductase enzyme This enzyme was ultimately to be delivered in a tumor specific manner by conjugating it to a tumor specific antibody. This approach is known generally as ADEPT.
  • a nitrobenzyl group is not capable of being reduced by mammalian enzymes given its low reduction potential. No mention is made in either the journal paper (Sagnou,M.J., Bioorganic and Medicinal Letters, 2000, 10,2082) or patent US 6608192 Bl and related filings as to the targeting of the hypoxic zones of tumors using a hypoxic specific release mechanism. We envision prodrugging the anthramycin series using the same reagents as described above for barminomycin.
  • R 2 is H or an alkyl group such a methyl depending on the solvent prefreatment (water, methanol or another alcohol) of the anthramycin and where Ri is shown below in analogous fashion to the barminomycin example with the asterisk being the attachment to the nitrogen of the hemiaminal.
  • the alcohol The reduction of the ester functionality to a primary alcohol was performed following a hydrolysis of the ester to the acid.
  • reaction mixture was filtered upon a pad of anhyd Na 2 SO 4 , volatiles removed in a rotary evaporator, and the residue purified on silica-gel column chromotograph using ethyl acetate to yield an essentially pure solid which was recrystalized from EtOAc-hexanes to yield the pure product.
  • the product was characterized by LC-MS showing one significant peak at the appropriate molecule weight and by HI NMR
  • Example 8 Syntheses of the bromides: [0237]
  • the bromides can be easily prepared from the corresponding alcohols prepared according to Examples 7 and 1 by way of several methods known in literature. In one such method, a solution of N-l-methyl-2-nitro-5- hydroxymethyl-imidazole (1 eq, 1.8 Molar) and dusopropylethylamine (2 eq) in anhyd CH 2 C1 2 was added to a solution of PPh 3 -Br 2 complex (commercial or in soln prepared in situ, 3.5 Molar ) while maintaining 0 C and the reaction mixture stirred at 0 C until TLC analysis showed complete disappearance of starting material. Volatiles were removed in vacuo and the residue was purified by silica gel chromotograph to yield the desired bromide, reagent B. The product were characterized by
  • Example 14 Biological Testing The following biological assays were used to characterize various of the protected anti- neoplastic agents. A) Clonogenic Toxicity Assay Introduction
  • the clonogenic assay measures the reproductive ability of a surviving cell by specifically determining if a cell can grow to form a colony of greater than 50 cells. Briefly, cells are treated with a drug for an acute exposure and then the drug is removed. Cells are trypinized to form single cell suspensions and known numbers of cells are plated and incubated until colonies form. Colonies are counted and the cell survival is calculated based on number of colonies formed in the treated groups compared to number of colonies formed in the untreated controls. In order to determine if a drug is selectively toxic under anoxic conditions cells are exposed to the drug either with air (normoxic) or completely without oxygen (anoxia). The terms aerobic and normoxic are used interchangeably.
  • Vessels were evacuated and gassed with either a certified anoxic gas mixture (95% nitrogen and 5 % carbon dioxide) or with aerobic gas mixture (95% air and 5% carbon dioxide). Specifically, each vessel was evacuated to minus 26 inches of mercury and held for 15 seconds before gassing at 20psi and again holding for 15 seconds. After a series of five evacuations and gassings the vessels were held an additional 5 minutes before a final evacuation and refilling of each vessel with the desired gas mixture at 0.5psi above atmospheric pressure. Cells were incubated for 2 hours at 37°C. At the end of treatment, plates were removed from each vessel and the drug promptly removed from the cells.
  • a certified anoxic gas mixture (95% nitrogen and 5 % carbon dioxide
  • aerobic gas mixture 95% air and 5% carbon dioxide
  • the daunorubicin control showed no significant toxicity difference in the above clonogenic assay ( 2 hr compound exposure) between normoxic( air) and anoxic conditions.
  • the IC 90 90% inhibition of colony formation was 0.5 micromolar with data ranges of 0.2 micromolar to 1 micromolar over multiple experiments
  • Example 9 showed under the same hypoxic conditions an IC 90 of 4 micromolar with data ranges of 2 micromolar to 5 micromolar over multiple experiments.
  • the normoxic data was very dramatic with no toxicity being seen at the highest concentration of 20 micromolar, the limit of solubility in cell media for this assay.
  • the compound of Example 9 showed a marked lack of toxicity under normal air conditions, implying the Example 9 compound is a very selective compound.
  • Example 10 showed under the same hypoxic conditions an IC 90 of 1 micromolar with data ranges of 0.5 micromolar to 2 micromolar over multiple experiments.
  • the normoxic data was very dramatic with no toxicity being seen at the highest concentration of 10 micromolar, the limit of solubility in cell media for this assay.
  • the compound of Example 10 showed a marked lack of toxicity under normal air conditions, implying the Example 10 compound is a very selective compound.
  • Example 11 showed under the same hypoxic conditions an IC 90 of 1 micromolar in one experiment. Under normoxic conditions the IC50 was approximately 5 micromolar in one experiment. The compound of Example 11 thus demonstrates good selectivity between anoxic and normoxic conditions.
  • Example 15 Prodrugs of Doxorubicin and Related Compounds The following is a prophetic example of protected anti-neoplastic agents as described in this patent:
  • This Example describes illustrative protected anti-neoplastic agents that release highly cytotoxic derivatives of doxorubicin.
  • doxorubicin, epirubicin, and daunomycin and the numerous analogs and derivatives of those compounds that have been and continue to be synthesized represent a class of compounds that can be readily converted into protected anti-neoplastic agents based on the teachings herein.
  • This example illustrates such protected anti-neoplastic agents that release highly cytotoxic compounds under hypoxic conditions. Highly cytotoxic daunomycin derivatives are described in the reference Bakina and Farquhar, 1999, Anti-cancer Drug Design 14: 507, incorporated herein by reference.
  • Part A of this Example illustrates a protected anti- neoplastic agents that releases such a highly cytotoxic derivative, referred to herein as a doxorubicin derivative, and that comprises one hypoxia-activated moiety.
  • Part B of this Example illustrates such a prodrug that comprises more than one such moiety.
  • Part C of this Example illustrates such a prodrug that releases a novel dicationic derivative.
  • the single free amino group of doxorubicin, daunomycin, epirubicin, and derivatives thereof having only this single free amino group can be readily modified with a hypoxic activator as described herein to yield protected anti-neoplastic agents having the following structure (DOX is doxorubicin or one of the related compounds previously mentioned other than the free amino group):
  • hypoxia-activated moiety is removed, releasing the following highly cytotoxic compound shown as iminium DOX (or Super Dox), below.
  • Part B Hypoxia-activated Doxorubicin Derivative Prodrug that Requires Removal of Multiple Hypoxia-activated Moieties.
  • the methodology described in part A of this example can be used to generate protected anti-neoplastic agents that have two or more hypoxia-activated moieties.
  • One illustrative protected anti-neoplastic agent having three such moieties is shown below (X is defined in part C).
  • Doxorubicin can be derivatized in accordance with a synthetic method as described herein with an aminoethyl moiety to generate a dicationic doxorubicin derivative that is highly cytotoxic and binds more tightly to DNA than doxorubicin.
  • a protected anti-neoplastic agent has the following structure (in the structure below, X represents any of the diverse moieties present in doxorubicin, daunomycin, epirubicin, and their naturally occurring and synthetic derivatives):
  • the prodrug is formed by reacting doxorubicin or a doxorubicin derivative with HC(0)CH 2 NHC0 2 R, where R is defined as above, first in the presence of NaB(OAc) 3 H and then in the presence of R'C0 2 C1, where R' is C 1-6 lower alkyl, and base.
  • Example 16 Prodrugs of Etoposide The following is a prophetic example of protected anti-neoplastic agents as described in this patent.
  • Etoposide is a potent non-intercalating DNA topoisomerase II inhibitor.
  • hypoxia- activated moiety is attached to the etoposide at the phenolic hydroxy positions via an ether linker.
  • linkers can be provided by other useful intermediate reagents as described herein, shown below. These reagents can be readily prepared from the corresponding alcohol
  • Example 17 Prodrugs of Vinca Alkaloids The following is a prophetic example of protected anti-neoplastic agents as described in this patent.
  • Protected anti-neoplastic agents that release vinblastine (or another vinca alkaloid) can be prepared from vinblastine (or another vinca alkaloid) as shown in the scheme below (the indole NH can be attached to the hypoxia-activated moiety selectively over attachment at the hydroxyls) using synthetic methodology substantially similar to that described in Example 16
  • At least one R is H
  • Vincristine-releasing protected anti-neoplastic agents are prepared in an analogous manner, starting with vincristine.
  • Example 18 Prodrugs of Topotecan The following is a prophetic example of protected anti-neoplastic agents as described in this patent. [0276] Protected anti-neoplastic agents that release topotecan can be prepared from topotecan as shown in the scheme below using synthetic methodology substantially similar to that described in Example 16.
  • Example 19 Prodrugs of Taxanes The following is a prophetic example of protected anti-neoplastic agents as described in this patent.
  • Protected anti-neoplastic agents that release paclitaxel, docetaxel, or another taxane can be prepared from paclitaxel (or docetaxel or another taxane) using synthetic methodology substantially similar to that described in Example 16 to prepare compounds similar in structure to the structure shown below.
  • such protected anti-neoplastic agents can have one, two, three, or four hypoxia-activated moieties.
  • these hypoxia-activated moieties are selected from those shown below.
  • Example 21 Prodrugs of 5-FU The following is a prophetic example of protected anti-neoplastic agents as described in this patent.
  • Protected anti-neoplastic agents that release 5-fluorouracil can be prepared from 5-FU using synthetic methodology substantially similar to that described in Example 16.
  • One such prodrug has the structure shown below.
  • Another protected anti-neoplastic agent has two hypoxia-activated moieties attached, one as shown in the structure above, and the other to the other ring nitrogen.
  • Example 21 Prodrugs of Alkylating Agents The following is a prophetic example of protected anti-neoplastic agents as described in this patent.
  • Protected anti-neoplastic agents that release an alkylating agent can be prepared from as shown in the scheme below using synthetic methodology substantially similar to that described in Example 16.
  • a protected anti-neoplastic agents of cyclophosphamide is used to illustrate this aspect of the compounds and methods described herein.
  • This protected anti- neoplastic agents can be synthesized in accordance with the methods described herein using the following illustrative synthetic method.
  • Example 22 Prodrugs of Hydroxyurea The following is a prophetic example of protected anti-neoplastic agents as described in this patent.
  • HU hydroxyurea
  • HU protected anti-neoplastic agents that release hydroxyurea
  • HU hydroxyurea
  • synthetic methodology substantially similar to that described in Example 16.
  • HU sold as Hydrea by Bristol-Myers Squibb
  • HU is an anti-leukemic drug with a mechanism of action ascribed to the inhibition of the DNA synthesizing enzyme ribonucleoside reductase.
  • HU has also been shown to be effective against brain tumors (meningioma).
  • Example 23 Nitroimidazole-20-Camptothecin prodrugs The following is a prophetic example of protected anti-neoplastic agents as described in this patent.
  • the N methylacetate moiety on the imidazole can be synthesized by demethylating the hydroxymethyl imidazole derivative with hydroiodic acid and realkylating it with methyl bromoacetate. Upon prodrug formation, the methoxy ester is removed, optionally with sodium hydroxide followed by acid treatment to restore the active lactone of camptothecin.
  • the camptothecin lactone can be hydrolyzed to the open form and the alcohol moiety derivatized with a chloromethyl nitroimidazole or chloromethoxymethyl nitroimidazole derivative.
  • This nitroimidazole derivative need not bear a carboxylic acid group off of the 1 position on the imidazole but can be rendered stable to two electron reduction by DT diaphorase by having a sterically hindered alkyl group, as discussed above.
  • This reaction can be carried out by the bis alkylation of the free carboxylic acid and the alcohol followed by basic hydrolysis of the ester, leaving a free acid for solubility and the nitroimidazole prodrug moiety masking the essential alcohol functionality.
  • Prodrug release under hypoxic conditions in vivo will result in the release of the alcohol.
  • Subsequent cyclization with the carboxylic acid under the acidic conditions of the tumor will generate an active camptothecin.
  • Such analogs of camptothecin can be prepared analogously, using any of the numerous camptothecin analogs known in the art as the drug to protected to yield a protected anti-neoplastic agent.
  • Example 24 Nitroimidazole Prodrugs of Duocarmycin The following is a prophetic example of protected anti-neoplastic agents as described in this patent. [0285] Many duocarmycin analogs and their prodrugs are known (see U.S. patent No. 5,985,909, PCT patent publication No. US02/17210, and U.S. patent application publication No. 2003/0050331 Al). None of these analogs or prodrugs employ a nitroimidazole triggered to release the duocarmycin using a stable ether connection to the phenolic group of the duocarmycin.
  • a representative example of a nitroimidazole duocarmycin protected anti- neoplastic agent is shown below, in which the phenolic oxygen is protected as an ether with the nitroimidazole as shown.
  • the synthesis starts, in one version, with the free duocarmycin phenol and the nitroimidazole derivative bearing a bromomethyl or chloromethyl group as the precursor to the ether connection.
  • Ri can be H, methyl or lower alkyl
  • R 2 can be COOR
  • X can be Cl, Br, I or sulfonate
  • R 3 and R 4 can be as described in PCT/US02/17210.
  • the R 5 group on the nitroimidazole can be methyl or a hindered alkyl as described above.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nanotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biophysics (AREA)
  • Immunology (AREA)
  • Neurology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Molecular Biology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Medical Informatics (AREA)
  • Endocrinology (AREA)
  • Urology & Nephrology (AREA)
  • Biotechnology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Dermatology (AREA)
  • Reproductive Health (AREA)
  • Oncology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Ophthalmology & Optometry (AREA)
  • Neurosurgery (AREA)
  • Pulmonology (AREA)
  • Biomedical Technology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des promédicaments activés par l'hypoxie que l'on peut utiliser pour traiter le cancer lors de leur administration seuls ou combinés à un ou plusieurs agents anti-néoplasiques.
PCT/US2004/009667 2003-03-28 2004-03-29 Compositions et methodes de traitement du cancer WO2004087075A2 (fr)

Priority Applications (12)

Application Number Priority Date Filing Date Title
EP04749522A EP1622608A4 (fr) 2003-03-28 2004-03-29 Compositions et methodes de traitement du cancer
NZ543223A NZ543223A (en) 2003-03-28 2004-03-29 Compositions and methods for treating cancer
EP13178249.2A EP2671581B8 (fr) 2003-03-28 2004-03-29 Compositions et procédés pour le traitement du cancer
KR1020127002215A KR101198526B1 (ko) 2003-03-28 2004-03-29 암 치료를 위한 조성물 및 방법
JP2006509466A JP2006521409A (ja) 2003-03-28 2004-03-29 癌を処置するための組成物および方法
AU2004226338A AU2004226338C1 (en) 2003-03-28 2004-03-29 Compositions and methods for treating cancer
MXPA05010407A MXPA05010407A (es) 2003-03-28 2004-03-29 Composiciones y metodos para tratar el cancer.
CA2520000A CA2520000C (fr) 2003-03-28 2004-03-29 Compositions et methodes de traitement du cancer
US10/549,545 US7550496B2 (en) 2003-03-28 2004-03-29 Compositions and methods for treating cancer
IL170970A IL170970A (en) 2003-03-28 2005-09-19 Nitroimidazolyl alkyl protected antineoplastic agents and their use in the preparation of anticancer medicaments
NO20054988A NO336266B1 (no) 2003-03-28 2005-10-26 Beskyttet anti-neoplastisk middel omfattende en eller flere beskyttbare hydroksylgrupper, anvendelse derav samt sammensetning inneholdende midlet
US12/484,104 US8299088B2 (en) 2003-03-28 2009-06-12 Compositions and methods for treating cancer

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US45884503P 2003-03-28 2003-03-28
US60/458,845 2003-03-28
US46528103P 2003-04-21 2003-04-21
US60/465,281 2003-04-21

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/484,104 Continuation US8299088B2 (en) 2003-03-28 2009-06-12 Compositions and methods for treating cancer

Publications (2)

Publication Number Publication Date
WO2004087075A2 true WO2004087075A2 (fr) 2004-10-14
WO2004087075A3 WO2004087075A3 (fr) 2005-03-24

Family

ID=33135116

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2004/009667 WO2004087075A2 (fr) 2003-03-28 2004-03-29 Compositions et methodes de traitement du cancer

Country Status (14)

Country Link
US (2) US7550496B2 (fr)
EP (2) EP1622608A4 (fr)
JP (2) JP2006521409A (fr)
KR (2) KR101198526B1 (fr)
CN (2) CN1791403A (fr)
AU (1) AU2004226338C1 (fr)
CA (1) CA2520000C (fr)
ES (1) ES2759176T3 (fr)
IL (1) IL170970A (fr)
MX (1) MXPA05010407A (fr)
NO (1) NO336266B1 (fr)
NZ (1) NZ543223A (fr)
WO (1) WO2004087075A2 (fr)
ZA (1) ZA200507752B (fr)

Cited By (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005086951A2 (fr) * 2004-03-10 2005-09-22 Threshold Pharmaceuticals, Inc. Agents anticancereux actives par l'hypoxie
WO2006095636A1 (fr) * 2005-03-10 2006-09-14 Kyoto University Nouveau compose active selectivement sur le site cible et utilisation dudit compose
US7208611B2 (en) 2005-02-23 2007-04-24 Xenoport, Inc. Platinum-containing compounds exhibiting cytostatic activity, synthesis and methods of use
WO2008083101A1 (fr) 2006-12-26 2008-07-10 Threshold Pharmaceuticals, Inc. Promédicaments d'alkylation de phosphoramidate pour le traitement du cancer
JP2009502743A (ja) * 2005-06-29 2009-01-29 スレッシュホールド ファーマシューティカルズ， インコーポレイテッド ホスホルアミデートアルキル化剤プロドラッグ
US7691838B2 (en) 2003-05-30 2010-04-06 Kosan Biosciences Incorporated Method for treating diseases using HSP90-inhibiting agents in combination with antimitotics
WO2010048330A1 (fr) 2008-10-21 2010-04-29 Threshold Pharmaceuticals, Inc. Traitement du cancer à l’aide de promédicaments activés par l’hypoxie
WO2012009288A2 (fr) 2010-07-12 2012-01-19 Threshold Pharmaceuticals, Inc. Administration de promédicaments activés par hypoxie et d'agents anti-angiogéniques pour le traitement du cancer
US8299088B2 (en) 2003-03-28 2012-10-30 Threshold Pharmaceuticals, Inc. Compositions and methods for treating cancer
US8410075B2 (en) 2007-03-19 2013-04-02 Cascade Prodrug Inc. Mannich base N-oxide drugs
WO2013096687A1 (fr) 2011-12-22 2013-06-27 Threshold Pharmaceuticals, Inc. Administration de promédicaments activés par l'hypoxie en combinaison à des inhibiteurs de chk1 pour le traitement du cancer
WO2013122112A1 (fr) 2012-02-13 2013-08-22 国立大学法人筑波大学 Promédicament à base de nitroimidazole
WO2014058974A1 (fr) * 2012-10-10 2014-04-17 Emory University Méthodes de gestion d'inflammation au moyen d'inhibiteurs de la voie de la glycolyse
WO2014150261A1 (fr) 2013-03-15 2014-09-25 Global Blood Therapeutics, Inc. Composés et leurs utilisations pour la modulation d'hémoglobine
WO2015013448A1 (fr) 2013-07-26 2015-01-29 Threshold Pharmaceuticals, Inc. Traitement d'un cancer du pancréas au moyen d'une combinaison d'un promédicament activé par l'hypoxie et d'un taxane
US8952171B2 (en) 2013-03-15 2015-02-10 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9402820B2 (en) 2011-04-22 2016-08-02 The United States Of America As Represented By The Secretary, Department Of Health And Human Services Use of pyruvate or succinate to enhance the efficacy of a hypoxia activated prodrug for the treatment of tumors
US9604999B2 (en) 2013-03-15 2017-03-28 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9802900B2 (en) 2013-03-15 2017-10-31 Global Blood Therapeutics, Inc. Bicyclic heteroaryl compounds and uses thereof for the modulation of hemoglobin
US9957250B2 (en) 2013-03-15 2018-05-01 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9981939B2 (en) 2013-03-15 2018-05-29 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10004725B2 (en) 2015-03-30 2018-06-26 Global Blood Therapeutics, Inc. Methods of treatment
US10017491B2 (en) 2013-03-15 2018-07-10 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10034879B2 (en) 2011-12-28 2018-07-31 Global Blood Therapeutics, Inc. Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation
US10077249B2 (en) 2016-05-12 2018-09-18 Global Blood Therapeutics, Inc. Process for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde
US10100040B2 (en) 2013-03-15 2018-10-16 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10100043B2 (en) 2013-03-15 2018-10-16 Global Blood Therapeutics, Inc. Substituted aldehyde compounds and methods for their use in increasing tissue oxygenation
US10131683B2 (en) 2014-07-17 2018-11-20 Molecular Templates, Inc. TH-302 solid forms and methods related thereto
US10137118B2 (en) 2014-02-07 2018-11-27 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US10266551B2 (en) 2013-03-15 2019-04-23 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10364261B2 (en) 2015-03-10 2019-07-30 Obi Pharma, Inc. DNA alkylating agents
US10377741B2 (en) 2011-12-28 2019-08-13 Global Blood Therapeutics, Inc. Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation
US10409869B2 (en) 2012-10-29 2019-09-10 Obi Pharma, Inc. (R)- and (S)-1-(3-(3-N,N-dimethylaminocarbonyl)phenoxyl-4-nitrophenyl)-1-ethyl-N,N'-bis (ethylene)phosphoramidate, compositions and methods for their use and preparation
US10450269B1 (en) 2013-11-18 2019-10-22 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10493035B2 (en) 2016-10-12 2019-12-03 Global Blood Therapeutics, Inc. Tablets comprising 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US10668047B2 (en) 2015-06-24 2020-06-02 Molecular Templates, Inc. Aziridine containing DNA alkylating agents
US20200261414A1 (en) * 2017-09-14 2020-08-20 Lankenau Institute For Medical Research Methods and compositions for the treatment of cancer
US10829437B2 (en) 2015-04-02 2020-11-10 Obi Pharma, Inc. Nitrobenzyl derivatives of anti-cancer agents
US11014884B2 (en) 2018-10-01 2021-05-25 Global Blood Therapeutics, Inc. Modulators of hemoglobin
US11020382B2 (en) 2015-12-04 2021-06-01 Global Blood Therapeutics, Inc. Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11236109B2 (en) 2013-03-15 2022-02-01 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
WO2023025312A1 (fr) 2021-08-27 2023-03-02 深圳艾欣达伟医药科技有限公司 Patient résistant aux inhibiteurs de parp traités avec th-302
WO2023025291A1 (fr) 2021-08-27 2023-03-02 深圳艾欣达伟医药科技有限公司 Solution de formulation lyophilisée, formulation lyophilisée, procédé et utilisation associés

Families Citing this family (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2278115T3 (es) * 2003-10-13 2007-08-01 Zoser B. Nat.Rer.Dr. Salama Composicion farmaceutica que comprende oxoplatino y sus sales.
GB0421296D0 (en) * 2004-09-24 2004-10-27 Angiogene Pharm Ltd Bioreductively-activated prodrugs
WO2008151253A1 (fr) * 2007-06-04 2008-12-11 Threshold Pharmaceuticals, Inc. Promédicaments d'agents antinéoplasiques activés par l'hypoxie
WO2009018163A1 (fr) * 2007-07-27 2009-02-05 Threshold Pharmaceuticals, Inc. Promédicaments d'anthracyclines activés par une hypoxie
WO2009033165A1 (fr) * 2007-09-06 2009-03-12 Threshold Pharmaceuticals, Inc. Promédicaments activés par l'hypoxie à base d'agents bis-alkylants
US20090118031A1 (en) * 2007-11-01 2009-05-07 Qualizza Gregory K Shaft Structure with Configurable Bending Profile
WO2010073126A2 (fr) * 2008-12-22 2010-07-01 The Governors Of The University Of Alberta Composés utiles dans l'administration d'une thérapie antinéoplasique et en imagerie diagnostique de cellules hypoxiques et procédés pour les utiliser
CN101538256B (zh) * 2009-04-28 2014-05-21 沈阳药科大学 3，4-二芳基呋喃-2，5-二酮类衍生物与3，4-二芳基-1h-吡咯-2，5-二酮类衍生物及其用途
GB0907551D0 (en) 2009-05-01 2009-06-10 Univ Dundee Treatment or prophylaxis of proliferative conditions
CA2820245A1 (fr) * 2010-12-06 2012-06-14 Merrimack Pharmaceuticals, Inc. Determination de la dose et administration pour la prevention de la cardiotoxicite dans le traitement par immunoliposomes ciblant erbb2 comprenant des agents chimiotherapeutiques a base d'anthracycline
CN102260273B (zh) * 2011-05-13 2015-04-22 兰州大学 脱氧鬼臼与5-氟尿嘧啶的拼合物及其制备与用途
CN110711188A (zh) 2012-01-20 2020-01-21 德玛公司 经取代的己糖醇类用于治疗恶性肿瘤的用途
KR20150005557A (ko) 2012-03-30 2015-01-14 우베 고산 가부시키가이샤 블록기를 갖는 폴리로탁산의 제조 방법
WO2014062856A1 (fr) 2012-10-16 2014-04-24 Halozyme, Inc. Hypoxie et hyaluronane et leurs marqueurs pour le diagnostic et la surveillance de maladies et de pathologies, et méthodes associées
US9913901B2 (en) 2012-12-03 2018-03-13 Merrimack Pharmaceuticals, Inc. Combination therapy for treating HER2-positive cancers
EP2777694A1 (fr) 2013-03-14 2014-09-17 Brij P. Giri Micelles polymériques pour le ciblage d'hypoxie dans l'imagerie et la thérapie du cancer
KR20160061911A (ko) 2013-04-08 2016-06-01 데니스 엠. 브라운 최적하 투여된 화학 화합물의 치료 효과
WO2014181314A1 (fr) 2013-05-10 2014-11-13 Department Of Biotechnology Ciblage cellulaire médié par un promoteur de phosphatase alcaline d'origine placentaire (plap)
KR20160099081A (ko) 2013-07-26 2016-08-19 업데이트 파마 인코포레이트 비산트렌의 치료 효과 개선용 조합 방법
CN104434876B (zh) * 2013-09-13 2018-04-27 布里吉·P·吉里 用于癌症疗法及成像的缺氧-标靶聚合微胞
WO2015154064A2 (fr) 2014-04-04 2015-10-08 Del Mar Pharmaceuticals Utilisation de dianhydrogalactitol et de leurs analogues ou dérivés dans le traitement du carcinome non à petites cellules des poumons et du cancer des ovaires
RU2018113280A (ru) 2015-09-16 2019-10-16 ДиЭфБи СОРИА, ЭлЭлСи Доставка наночастиц лекарственного средства и способы их использования
CN105250325A (zh) * 2015-10-28 2016-01-20 淄博齐鼎立专利信息咨询有限公司 Demissine在制备治疗肾癌药物中的应用
CN106554375B (zh) * 2016-06-08 2019-10-18 浙江海正药业股份有限公司 一种蒽环类化合物、其制备方法及其用途
WO2018170196A1 (fr) 2017-03-15 2018-09-20 Dfb Soria, Llc Thérapie topique pour le traitement de malignités cutanées au moyen de nanoparticules de taxanes
CN106977501A (zh) * 2017-03-20 2017-07-25 华东师范大学 一种基于2‑硝基咪唑‑1‑烷基醇的低氧激活前药
CN107417672A (zh) * 2017-04-12 2017-12-01 华东师范大学 一种基于2,2‑二甲基‑3‑（2‑硝基咪唑基）丙酸的低氧激活前药
EP3746134A1 (fr) 2018-02-02 2020-12-09 Maverix Oncology, Inc. Conjugués de médicaments à petites molécules de monophosphate de gemcitabine
US11497726B2 (en) 2018-03-16 2022-11-15 Dfb Soria, Ll. Topical therapy for the treatment of cervical intraepithelial neoplasia (CIN) and cervical cancer using nanoparticles of taxanes
KR20230023463A (ko) 2021-08-10 2023-02-17 경북대학교 산학협력단 두경부암의 예후 예측을 위한 암 관련 섬유아세포의 바이오마커
CN113968867A (zh) * 2021-11-10 2022-01-25 聊城大学 一种喜树碱类前药及其用途
CN114617876B (zh) * 2022-01-28 2023-04-07 四川大学华西医院 一种抗肿瘤联合用药物
CN116675620A (zh) * 2022-02-22 2023-09-01 东南大学 No供体化合物及其制备方法、药物组合物和应用

Family Cites Families (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3652579A (en) * 1969-06-26 1972-03-28 Hoffmann La Roche 1-methyl-2-substituted 5-nitroimidazoles
DE2229223C3 (de) 1971-07-30 1975-12-18 Gruppo Lepetit S.P.A., Mailand (Italien) 2-Nitro-S-imidazol-Derivate und Verfahren zu deren Herstellung
US4921963A (en) 1987-04-13 1990-05-01 British Columbia Cancer Foundation Platinum complexes with one radiosensitizing ligand
JPH0819111B2 (ja) * 1987-10-22 1996-02-28 ポーラ化成工業株式会社 ２―ニトロイミダゾール誘導体及びこれを有効成分とする放射線増感剤
US4908356A (en) * 1988-05-25 1990-03-13 Research Corporation Technologies, Inc. Aldophosphamide derivatives useful as antitumor agents
US5190929A (en) * 1988-05-25 1993-03-02 Research Corporation Technologies, Inc. Cyclophosphamide analogs useful as anti-tumor agents
US5403932A (en) * 1988-05-25 1995-04-04 Research Corporation Technologies, Inc. Phosphoramidates useful as antitumor agents
DE3835772A1 (de) * 1988-10-20 1990-04-26 Deutsches Krebsforsch Tumorhemmende saccharid-konjugate
KR927003539A (ko) * 1990-01-26 1992-12-18 스즈끼 쯔네시 2-니트로 이미다졸 유도체, 그의 제조방법 및 이를 유효성분으로 하는 방사선 증감제
US5233031A (en) 1991-09-23 1993-08-03 University Of Rochester Phosphoramidate analogs of 2'-deoxyuridine
WO1993008288A1 (fr) * 1991-10-23 1993-04-29 Cancer Research Campaign Technology Limited Nitroreductase bacterienne pour la reduction de cb 1954 et analogues de ceux-ci en une forme cytotoxique
US5750782A (en) * 1992-11-27 1998-05-12 Cancer Research Campaign Technology Limited Nitroaniline derivatives and their use as anti-tumour agents
US5306727A (en) * 1993-04-30 1994-04-26 Research Corporation Technologies, Inc. Phosphoramidates useful as antitumor agents
AU6859394A (en) * 1993-05-25 1994-12-20 Auckland Uniservices Limited Nitrobenzyl mustard quaternary salts and their use as hypoxia-selective cytotoxic agents
DE69425356T2 (de) 1993-09-22 2002-04-18 Hoechst Ag Pro-Prodrugs, ihre Herstellung und Anwendung
JPH07309761A (ja) * 1994-05-20 1995-11-28 Kyowa Hakko Kogyo Co Ltd デュオカルマイシン誘導体の安定化法
US5659061A (en) 1995-04-20 1997-08-19 Drug Innovation & Design, Inc. Tumor protease activated prodrugs of phosphoramide mustard analogs with toxification and detoxification functionalities
GB9516943D0 (en) * 1995-08-18 1995-10-18 Cancer Soc Auckland Div Nz Inc Novel cyclopropylindoles and their secoprecursors,and their use as prodrugs
GB9526391D0 (en) 1995-12-22 1996-02-21 Diversey Equipment Technologie Dispenser
US6218519B1 (en) 1996-04-12 2001-04-17 Pro-Neuron, Inc. Compounds and methods for the selective treatment of cancer and bacterial infections
US6130237A (en) * 1996-09-12 2000-10-10 Cancer Research Campaign Technology Limited Condensed N-aclyindoles as antitumor agents
US6251933B1 (en) * 1996-12-13 2001-06-26 The Cancer Research Campaign Technology Limited Seco precursors of cyclopropylindolines and their use as prodrugs
DE19720312A1 (de) * 1997-05-15 1998-11-19 Hoechst Ag Zubereitung mit erhöhter in vivo Verträglichkeit
GB9818730D0 (en) 1998-08-27 1998-10-21 Univ Portsmouth Collections of compounds
US6240925B1 (en) * 1999-03-23 2001-06-05 Cynosure, Inc. Photothermal vascular targeting with bioreductive agents
GB9909612D0 (en) 1999-04-26 1999-06-23 Cancer Res Campaign Tech N-protected amines and their use as prodrugs
EP1185276B1 (fr) 1999-05-24 2003-12-10 Southern Research Institute Analogues d'yperite d'isophosphoramide et utilisation de ceux-ci
AU5935600A (en) * 1999-07-14 2001-01-30 Richard F. Borch Phosphoramide compounds
US6903081B2 (en) 2000-03-31 2005-06-07 Purdue Research Foundation Phosphoramidates and methods therefor
JP2002046334A (ja) 2000-08-04 2002-02-12 Riso Kagaku Corp 孔版印刷装置及び該装置の印刷ドラム
EP1243276A1 (fr) * 2001-03-23 2002-09-25 Franciscus Marinus Hendrikus De Groot Prodrogues activables à séparateurs allongés et multiples
US6506739B1 (en) 2001-05-01 2003-01-14 Telik, Inc. Bis-(N,N'-bis-(2-haloethyl)amino)phosphoramidates as antitumor agents
MXPA03011094A (es) * 2001-05-31 2004-12-06 Medarex Inc Citotoxinas, profarmacos, ligadores, y estabilizadores utiles para ello.
FR2825926A1 (fr) * 2001-06-14 2002-12-20 Sod Conseils Rech Applic Derives d'imidazoles modulant les canaux sodiques
US7091186B2 (en) * 2001-09-24 2006-08-15 Seattle Genetics, Inc. p-Amidobenzylethers in drug delivery agents
KR20030067275A (ko) 2002-02-07 2003-08-14 주식회사 하이폭시 니트로이미다졸 및 위상 이성질화 효소 저해제를유효성분으로 포함하는 항암제
JP4187096B2 (ja) 2003-01-15 2008-11-26 独立行政法人科学技術振興機構 ３次元フォトニック結晶製造方法
GB0306908D0 (en) 2003-03-26 2003-04-30 Angiogene Pharm Ltd Bioreductively activated stilbene prodrugs
GB0306907D0 (en) 2003-03-26 2003-04-30 Angiogene Pharm Ltd Boireductively-activated prodrugs
ZA200507752B (en) 2003-03-28 2007-01-31 Threshold Pharmaceuticals Inc Compositions and methods for treating cancer
US6855695B2 (en) * 2003-06-13 2005-02-15 Vion Pharmaceuticals, Inc. Water-soluble SHPs as novel alkylating agents
KR101226631B1 (ko) 2004-02-06 2013-01-28 쓰레솔드 파마슈티컬스, 인코포레이티드 항암 치료 방법
WO2006057946A2 (fr) 2004-11-22 2006-06-01 Threshold Pharmaceuticals, Inc. Agents anticancereux de liaison à la tubuline et leurs prodrogues
WO2008011588A2 (fr) 2006-07-20 2008-01-24 Threshold Pharmaceuticals, Inc. Glycoconjugués d'alkylateurs de phosphoramidate pour le traitement du cancer
WO2008076826A1 (fr) 2006-12-13 2008-06-26 Threshold Pharmaceuticals, Inc. Agents d'alkylation pyrophosphoramide
ES2884044T3 (es) 2006-12-26 2021-12-10 Immunogenesis Inc Profármaco alquilante de fosforamidato para el tratamiento del cáncer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of EP1622608A4 *

Cited By (70)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8299088B2 (en) 2003-03-28 2012-10-30 Threshold Pharmaceuticals, Inc. Compositions and methods for treating cancer
US7691838B2 (en) 2003-05-30 2010-04-06 Kosan Biosciences Incorporated Method for treating diseases using HSP90-inhibiting agents in combination with antimitotics
WO2005086951A3 (fr) * 2004-03-10 2006-03-30 Threshold Pharmaceuticals Inc Agents anticancereux actives par l'hypoxie
WO2005086951A2 (fr) * 2004-03-10 2005-09-22 Threshold Pharmaceuticals, Inc. Agents anticancereux actives par l'hypoxie
US7208611B2 (en) 2005-02-23 2007-04-24 Xenoport, Inc. Platinum-containing compounds exhibiting cytostatic activity, synthesis and methods of use
WO2006095636A1 (fr) * 2005-03-10 2006-09-14 Kyoto University Nouveau compose active selectivement sur le site cible et utilisation dudit compose
JP2006282653A (ja) * 2005-03-10 2006-10-19 Kyoto Univ 標的部位で選択的に活性化される新規化合物およびその利用
JP2009502743A (ja) * 2005-06-29 2009-01-29 スレッシュホールド ファーマシューティカルズ， インコーポレイテッド ホスホルアミデートアルキル化剤プロドラッグ
US8664204B2 (en) 2005-06-29 2014-03-04 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
US8003625B2 (en) 2005-06-29 2011-08-23 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
US8507464B2 (en) 2005-06-29 2013-08-13 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
JP2012153722A (ja) * 2005-06-29 2012-08-16 Threshold Pharmaceuticals Inc ホスホルアミデートアルキル化剤プロドラッグ
US9226932B2 (en) 2005-06-29 2016-01-05 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
WO2008083101A1 (fr) 2006-12-26 2008-07-10 Threshold Pharmaceuticals, Inc. Promédicaments d'alkylation de phosphoramidate pour le traitement du cancer
US8552048B2 (en) 2006-12-26 2013-10-08 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs for the treatment of cancer
US8410075B2 (en) 2007-03-19 2013-04-02 Cascade Prodrug Inc. Mannich base N-oxide drugs
WO2010048330A1 (fr) 2008-10-21 2010-04-29 Threshold Pharmaceuticals, Inc. Traitement du cancer à l’aide de promédicaments activés par l’hypoxie
EP3311835A1 (fr) 2010-07-12 2018-04-25 Threshold Pharmaceuticals Inc. Administration de promédicaments activés par hypoxie et d'agents anti-angiogéniques pour le traitement du cancer
WO2012009288A2 (fr) 2010-07-12 2012-01-19 Threshold Pharmaceuticals, Inc. Administration de promédicaments activés par hypoxie et d'agents anti-angiogéniques pour le traitement du cancer
US9402820B2 (en) 2011-04-22 2016-08-02 The United States Of America As Represented By The Secretary, Department Of Health And Human Services Use of pyruvate or succinate to enhance the efficacy of a hypoxia activated prodrug for the treatment of tumors
WO2013096687A1 (fr) 2011-12-22 2013-06-27 Threshold Pharmaceuticals, Inc. Administration de promédicaments activés par l'hypoxie en combinaison à des inhibiteurs de chk1 pour le traitement du cancer
US10806733B2 (en) 2011-12-28 2020-10-20 Global Blood Therapeutics, Inc. Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation
US10822326B2 (en) 2011-12-28 2020-11-03 Global Blood Therapeutics, Inc. Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation
US10377741B2 (en) 2011-12-28 2019-08-13 Global Blood Therapeutics, Inc. Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation
US10034879B2 (en) 2011-12-28 2018-07-31 Global Blood Therapeutics, Inc. Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation
US9655975B2 (en) 2012-02-13 2017-05-23 University Of Tsukuba Prodrug using nitroimidazole
WO2013122112A1 (fr) 2012-02-13 2013-08-22 国立大学法人筑波大学 Promédicament à base de nitroimidazole
WO2014058974A1 (fr) * 2012-10-10 2014-04-17 Emory University Méthodes de gestion d'inflammation au moyen d'inhibiteurs de la voie de la glycolyse
US10409869B2 (en) 2012-10-29 2019-09-10 Obi Pharma, Inc. (R)- and (S)-1-(3-(3-N,N-dimethylaminocarbonyl)phenoxyl-4-nitrophenyl)-1-ethyl-N,N'-bis (ethylene)phosphoramidate, compositions and methods for their use and preparation
US10017491B2 (en) 2013-03-15 2018-07-10 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US8952171B2 (en) 2013-03-15 2015-02-10 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9981939B2 (en) 2013-03-15 2018-05-29 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10858317B2 (en) 2013-03-15 2020-12-08 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9802900B2 (en) 2013-03-15 2017-10-31 Global Blood Therapeutics, Inc. Bicyclic heteroaryl compounds and uses thereof for the modulation of hemoglobin
US9776960B2 (en) 2013-03-15 2017-10-03 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10829470B2 (en) 2013-03-15 2020-11-10 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10100040B2 (en) 2013-03-15 2018-10-16 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10100043B2 (en) 2013-03-15 2018-10-16 Global Blood Therapeutics, Inc. Substituted aldehyde compounds and methods for their use in increasing tissue oxygenation
WO2014150261A1 (fr) 2013-03-15 2014-09-25 Global Blood Therapeutics, Inc. Composés et leurs utilisations pour la modulation d'hémoglobine
US11236109B2 (en) 2013-03-15 2022-02-01 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10266551B2 (en) 2013-03-15 2019-04-23 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10315991B2 (en) 2013-03-15 2019-06-11 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9957250B2 (en) 2013-03-15 2018-05-01 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9604999B2 (en) 2013-03-15 2017-03-28 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10435393B2 (en) 2013-03-15 2019-10-08 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11530191B2 (en) 2013-03-15 2022-12-20 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
WO2015013448A1 (fr) 2013-07-26 2015-01-29 Threshold Pharmaceuticals, Inc. Traitement d'un cancer du pancréas au moyen d'une combinaison d'un promédicament activé par l'hypoxie et d'un taxane
US10450269B1 (en) 2013-11-18 2019-10-22 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10722502B2 (en) 2014-02-07 2020-07-28 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US11452720B2 (en) 2014-02-07 2022-09-27 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US10137118B2 (en) 2014-02-07 2018-11-27 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US10131683B2 (en) 2014-07-17 2018-11-20 Molecular Templates, Inc. TH-302 solid forms and methods related thereto
US10654876B2 (en) 2014-07-17 2020-05-19 Molecular Templates, Inc. TH-302 solid forms and methods related thereto
US10766914B2 (en) 2015-03-10 2020-09-08 Obi Pharma, Inc. DNA alkylating agents
US10364261B2 (en) 2015-03-10 2019-07-30 Obi Pharma, Inc. DNA alkylating agents
US10695330B2 (en) 2015-03-30 2020-06-30 Global Blood Therapeutics, Inc. Methods of treatment
US10004725B2 (en) 2015-03-30 2018-06-26 Global Blood Therapeutics, Inc. Methods of treatment
US11535585B2 (en) 2015-04-02 2022-12-27 Obi Pharma, Inc. Nitrobenzyl derivatives of anti-cancer agents
US10829437B2 (en) 2015-04-02 2020-11-10 Obi Pharma, Inc. Nitrobenzyl derivatives of anti-cancer agents
US10668047B2 (en) 2015-06-24 2020-06-02 Molecular Templates, Inc. Aziridine containing DNA alkylating agents
US11020382B2 (en) 2015-12-04 2021-06-01 Global Blood Therapeutics, Inc. Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US11944612B2 (en) 2015-12-04 2024-04-02 Global Blood Therapeutics, Inc. Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US10577345B2 (en) 2016-05-12 2020-03-03 Global Blood Therapeutics, Inc. Process for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde
US10077249B2 (en) 2016-05-12 2018-09-18 Global Blood Therapeutics, Inc. Process for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde
US10493035B2 (en) 2016-10-12 2019-12-03 Global Blood Therapeutics, Inc. Tablets comprising 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US20200261414A1 (en) * 2017-09-14 2020-08-20 Lankenau Institute For Medical Research Methods and compositions for the treatment of cancer
US11014884B2 (en) 2018-10-01 2021-05-25 Global Blood Therapeutics, Inc. Modulators of hemoglobin
WO2023025312A1 (fr) 2021-08-27 2023-03-02 深圳艾欣达伟医药科技有限公司 Patient résistant aux inhibiteurs de parp traités avec th-302
WO2023025291A1 (fr) 2021-08-27 2023-03-02 深圳艾欣达伟医药科技有限公司 Solution de formulation lyophilisée, formulation lyophilisée, procédé et utilisation associés

Also Published As

Publication number Publication date
EP1622608A2 (fr) 2006-02-08
CN102161679A (zh) 2011-08-24
US20090312276A1 (en) 2009-12-17
ES2759176T3 (es) 2020-05-07
NO20054988D0 (no) 2005-10-26
ZA200507752B (en) 2007-01-31
EP2671581B1 (fr) 2019-10-02
KR20120035198A (ko) 2012-04-13
JP2006521409A (ja) 2006-09-21
US8299088B2 (en) 2012-10-30
NO20054988L (no) 2005-12-23
KR20050113670A (ko) 2005-12-02
US7550496B2 (en) 2009-06-23
WO2004087075A3 (fr) 2005-03-24
JP2012082227A (ja) 2012-04-26
IL170970A (en) 2012-01-31
EP2671581B8 (fr) 2019-11-13
EP2671581A3 (fr) 2014-01-01
KR101198526B1 (ko) 2012-11-06
AU2004226338A1 (en) 2004-10-14
EP2671581A2 (fr) 2013-12-11
US20060258656A1 (en) 2006-11-16
NO336266B1 (no) 2015-07-06
CA2520000C (fr) 2012-06-05
NZ543223A (en) 2008-11-28
JP5572644B2 (ja) 2014-08-13
CN1791403A (zh) 2006-06-21
CA2520000A1 (fr) 2004-10-14
EP1622608A4 (fr) 2010-11-10
MXPA05010407A (es) 2006-05-31
AU2004226338B2 (en) 2011-05-19
AU2004226338C1 (en) 2012-01-12

Similar Documents

Publication Publication Date Title
EP2671581B1 (fr) Compositions et procédés pour le traitement du cancer
US20080132458A1 (en) Hypoxia-Activated Anti-Cancer Agents
US8664204B2 (en) Phosphoramidate alkylator prodrugs
US20090042820A1 (en) Tubulin Binding Anti Cancer Agents And Prodrugs Thereof
US20080214576A1 (en) Topoisomerase Inhibitors and Prodrugs
US8309554B2 (en) Hypoxia activated drugs of nitrogen mustard alkylators
WO2007137196A2 (fr) Composés anti-cancéreux de liaison à la tubuline et promédicaments à base de tels composés

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 170970

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 2520000

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2004226338

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2005/07752

Country of ref document: ZA

Ref document number: 200507752

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: PA/a/2005/010407

Country of ref document: MX

Ref document number: 2006509466

Country of ref document: JP

Ref document number: 1921/KOLNP/2005

Country of ref document: IN

Ref document number: 01921/KOLNP/2005

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 1020057018367

Country of ref document: KR

REEP Request for entry into the european phase

Ref document number: 2004749522

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2004749522

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2004226338

Country of ref document: AU

Date of ref document: 20040329

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2004226338

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 543223

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 20048132768

Country of ref document: CN

WWP Wipo information: published in national office

Ref document number: 1020057018367

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 2004749522

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2006258656

Country of ref document: US

Ref document number: 10549545

Country of ref document: US

WWP Wipo information: published in national office

Ref document number: 10549545

Country of ref document: US